Fused azole-pyrimidine derivatives

ABSTRACT

The present invention relates to hovel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidylinositol-3-kinase (PI3K) inhibition, especially for PI3K-γ inhibition and can be used for the prophylaxis and treatment of diseases associated with PI3K and particularly with PI3K-γ activity. More specifically, the azole derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immunoregulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, autoixnmune pathologies such as rheumatoid arthritis, and Graves&#39; disease, cancer, myocardial contractility disorders, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the present invention are also useful for pulmonary hypertension, renal failure, cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson&#39;s disease, Alzheimer&#39;s disease, diabetes and focal ischemia, since the diseases also relate to PI3K activity in a human or animal subject.

DETAILED DESCRIPTION OF INVENTION TECHNICAL FIELD

The present invention relates to novel fused azolepyrimidinederivatives, processes for preparing them and pharmaceuticalpreparations containing them. The fused azolepyrimidine derivatives ofthe present invention exhibit enhanced potency forphosphotidylinositol-3-kinase (PI3K) inhibition, especially for PI3K-γinhibition and can be used for the prophylaxis and treatment of diseasesassociated with PI3K and particularly with PI3K-γ activity.

More specifically, the fused azolepyrimidine derivatives of the presentinvention are useful for treatment and prophylaxis of diseases asfollows: inflammatory and immunoregulatory disorders, such as asthma,atopic dermatitis, rhinitis, allergic diseases, chronic obstructivepulmonary disease (COPD), septic shock, joint diseases, autoimmunepathologies such as rheumatoid arthritis, and Graves' disease, cancer,myocardial contractility disorders, heart failure, thromboembolism,ischemia, and atherosclerosis.

The compounds of the present invention are also useful for pulmonaryhypertension, renal failure, cardiac hypertrophy, as well asneurodegenerative disorders such as Parkinson's disease, Alzheimer'sdisease, diabetes and focal ischemia, since the diseases also relate toPI3K activity in a human or animal subject.

BACKGROUND ART

Signal transduction pathways originating from chemoattractant receptorsare considered to be important targets in controlling leukocyte motilityin inflammatory diseases. Leukocyte trafficking is controlled bychemoattractant factors that activate heterotrimeric G-protein coupledreceptors (GPCRs) and thereby trigger a complex variety of downstreamintracellular events. Signal transduction at one of the pathways, thatresults in mobilization of intracellular free Ca²⁺, cytoskeletalreorganisation, and directional movement depends on lipid-derived secondmessengers produced by phosphoinositide 3-kinase (PI3K) activity [1,2].

PI3K phosphorylates the D3-hydroxyl position of the membranephospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P₂) toyield phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P₃). Basedon substrate specificity and protein structure, the PI3K familycomprises three classes [4-6]. Of particular interest in leukocytemigration are class I PI3Ks, which are all involved in receptor-inducedinflammatory cellular responses and are further divided into thesubclasses IA (p110α, β, δ) and IB (p110γ).

Class IA enzymes (p110α, β, δ) associate with a p85 adapter subunit,which contains two SH2 domains, to form a heterodimeric complex. Thiscomplex is able to recognize phosphotyrosine YxxM motifs, resulting inassociation with receptor tyrosine kinases and subsequent activation ofthe enzyme through receptor tyrosine kinases [1, 2]. The class IAsubtypes are considered to be associated with cell proliferation andcarcinogenesis. The IA subtypes bind to activated ras oncogene, which isfound in many cancers, to express their enzyme activity. It has alsofound that both p110α and β play important roles in human cancer growth[3].

Class IB (p110γ) enzyme, whose expression is largely confined toleukocytes, is activated by the G protein βγ complex, and functionsdownstream of seven transmembrane chemoattractant receptors [7-9]. Thep101 adapter protein, which bears no resemblance to any other knownprotein, is essential for the G protein βγ responsiveness of the p110γ(PI3Kγ). [10-12].

Recent studies in mice lacking functional PI3Kγ (PI3Kγ−/− mice), whichwere viable, fertile, and displayed a normal life span in a conventionalmouse facility, have revealed that neutrophils are unable to producePtdIns(3,4,5)P₃ when stimulated with GPCR agonists such as fMLP, C5a orIL-8. This demonstrates that PI3Kγ is the sole PI3K that is coupled tothese GPCRs in these cells [13-16]. Moreover, PtdIns(3,4,5)P₃-dependentactivation of protein kinase B (PKB) was also absent in thoseneutrophils, while PKB could still be activated by GM-CSF orIgG/C3b-coated zymosan via either p110α, β or δ. At the same time,G-protein-mediated responses such as PLCβ activation were intact.PI3Kγ−/− mice showed impaired thymocyte development and increases inneutrophil, monocyte, and eosinophil populations [14]. Furthermore,neutrophils and macrophages isolated from PI3Kγ−/− mice exhibited severedefects in migration and respiratory burst in response to GPCR agonistsand chemotactic agents [14,16]. Expression of PI3Kγ was also examined intransgenic mice expressing green fluorescence protein (GFP) under thecontrol of the endogenous PI3Kγ promoter. GFP was detected in spleen andbone marrow cells, and neutrophils, suggesting that the expression ofPI3Kγ is restricted to hematopoietic cells [15]. Collectively, the classIB phosphoinositide 3-kinase PI3Kγ seems to be pivotal in the control ofleukocyte trafficking and accordingly the development ofisotype-selective inhibitors of PI3Kγ should be an attractiveanti-inflammatory strategy.

Hypertrophic responses can be initiated by PI3K signaling pathways.Currently new research was published which identify a function forPTEN-PI3Kγ pathway in the modulation of heart muscle contractility.Whereas PI3Kα mediates the alteration in cell size seen during hearthyperthrophy up to heart failure, PI3Kγ acts as a negative regulator ofcardiac contractility.

PTEN is a dual-specificity protein phosphatase recently implicated as aphospho-inositide phosphatase in cellular growth signaling. The tumorsuppressor PTEN is shown to dephosphorylate phosphatidylinositol3,4,5-triphosphate (PIP3) which is an important second messengergenerated specifically by the actions of PI3K. The PTEN reduces thelevels of PIP3 within the cells and antagonizes PI3K mediated cellularsignaling. It is also reported that expression of dominant-negative PTENin rat cardiomyocytes in tissue culture results in hypertrophy.

PI3Kγ modulates baseline cAMP levels and controls contractility incells. This study also indicates that alterations in baseline cAMP levelcontribute to the increased contractility in mutant mice [17].

Therefore, this research result shows that PI3Kγ is involved inmyocardial contractility and therefore the inhibitors would be potentialtreatments of congestive heart failure, ischemia, pulmonaryhypertension, renal failure, cardiac hypertrophy, atherosclerosis,thromboembolism, and diabetes.

A inhibitor of PI3K, which is expected to block signaltranduction fromGPCR and the activation of various immune cells, should have a broadanti-inflammatory profile with potential for the treatment ofinflammatory and immunoregulatory disorders, [2] including asthma,atopic dermatitis, rhinitis, allergic diseases, chronic obstructivepulmonary disease (COPD), septic shock, joint diseases, autoimmunepathologies such as rheumatoid arthritis, and Graves' disease, diabetes,cancer, myocardial contractility disorders, thromboembolism [18], andatherosclerosis.

Some PI3-kinase inhibitors has been identified: wortmannin, originallyisolated as a fungal toxin from Penicillium wortmannii [19], the closelyrelated but less well characterized demethoxyviridin and LY294002, amorpholino derivative of the broad-spectrum kinase inhibitor quercetin[20].

U.S. Pat. No. 3,644,354 discloses 5-substituted2,3,dihydroimidazo[1,2-c]quinazolines represented by the generalformula:

wherein R and R⁰ is independently, hydrogen, lower alkyl, lower alkenyl;R′ and R″ are independently, hydrogen, halogen, lower alkyl, loweralkoxy or

as a hypotensive agents and coronary dilators

However, none of the references discloses fused azolepyrimidine such as,but not limited to, azole-quinazoline, azole-pyridopyrimidine,azole-pyrimidopyrimidine, azole-pyrimidopyridazine,azole-pyrimidotriazine, azole-pteridine, azole-pyrimidotetrazine andother derivatives having acylated amine or —CR⁵R⁶—C(O)— (R⁵is hydrogenor C₁₋₆ alkyl and R⁶ is halogen, hydrogen, or C₁₋₆ alkyl) linker at the5 or 6 position of the fused azolepyrimidine also having PI3K inhibitoryactivity.

The development of a compound which is useful for treatment andprophylaxis of inflammatory, cancer and/or myocardial contractilitydisorders associated with PI3K activity has been still desired.

SUMMARY OF THE INVENTION

As a result of extensive studies on chemical modification of the fusedazolepyrimidine derivatives, the present inventors have found that thecompounds of novel chemical structure related to the present inventionhave PI3K inhibitory activity and particularly have PI3K-γ inhibitoryactivity. The present invention has been accomplished based on thesefindings.

This invention is to provide novel fused azolepyrimidine derivatives ofthe formula (I) their tautomeric and stereoisomeric forms, and saltsthereof.

wherein

-   X represents CR⁵R⁶ or NH;-   Y¹ represents CR³ or N;-   Chemical bond between Y²═Y³ represents a single bond or double bond,-   with the proviso that when the Y²═Y³ represents a double bond,-   Y² and Y³ independently represent CR⁴ or N, and-   when Y²═Y³ represents a single bond, Y² and Y³ independently    represent CR³R⁴ or NR⁴;-   Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N;-   R¹ represents aryl optionally having 1 to 3 substituents selected    from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3 substituents    selected from R¹¹,    -   C₁₋₆ alkyl optionally substituted by    -   aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one        or more halogen,    -   C₁₋₆ alkoxy optionally substituted by    -   carboxy, aryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy,        heteroaryloxy or one or more halogen,    -   or    -   a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is        saturated or unsaturated, and contains 1 to 3 heteroatoms        selected from the group consisting of N, O and S, and optionally        having 1 to 3 substituents selected from R¹¹    -   wherein    -   R¹¹ represents    -   halogen, nitro, hydroxy, cyano, carboxy, amino,        N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,        N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,        N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl)amino,        N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,        N—(C₁₋₆alkoxycarbonyl)amino, N-[N,N-di(C₁₋₆alkyl)amino        methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino (C₁₋₆        alkyl)methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino        C₂₋₆alkenyl]amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,        N,N-di(C₁₋₆alkyl)aminocarbonyl, C₃₋₈cycloalkyl, C₁₋₆ alkylthio,        C₁₋₆alkanesulfonyl, sulfamoyl, C₁₋₆alkoxycarbonyl, N-arylamino        wherein said aryl moiety is optionally having 1 to 3        substituents selected from R¹⁰¹, N-(aryl C₁₋₆alkyl)amino wherein        said aryl moiety is optionally having 1 to 3 substituents        selected from R¹⁰¹, aryl C₁₋₆alkoxy-carbonyl wherein said aryl        moiety is optionally having 1 to 3 substituents selected from        R¹⁰¹,    -   C₁₋₆alkyl optionally substituted by mono-, di- or tri- halogen,        amino, N—(C₁₋₆alkyl)amino or N,N-di(C₁₋₆alkyl)amino,    -   C₁₋₆alkoxy optionally substituted by    -   mono-, di- or tri- halogen, N—(C₁₋₆alkyl)sulfonamide, or        N-(aryl)sulfonamide, or    -   a 5 to 7 membered saturated or unsaturated ring having 1 to 3        heteroatoms selected from the group consisting of O, S and N,        and optionally having 1 to 3 substituents selected from R¹⁰¹    -   wherein    -   R¹⁰¹ represents    -   halogen, carboxy, amino, N—(C₁₋₆ alkyl)amino,        N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,        N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl,        pyridyl,    -   C₁₋₆ alkyl optionally substituted by cyano or mono- di- or tri-        halogen,    -   or    -   C₁₋₆alkoxy optionally substituted by cyano, carboxy, amino,        N—(C₁₋₆ alkyl)amino, N,N-di(C₁₋₆alkyl)amino, aminocarbonyl,        N—(C₁₋₆alkyl)aminocarbonyl, N,N-di(C₁₋₆alkyl)aminocarbonyl or        mono-, di- or tri- halogen;-   R² represents hydroxy, halogen, nitro, cyano, amino,    N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,    N-(hydroxyC₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,    C₁₋₆ acyloxy, aminoC₁₋₆ acyloxy, C₂₋₆alkenyl, aryl, a 5-7 membered    saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms    selected from the group consisting O, S and N, and optionally    substituted by    -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, amino, amino C₁₋₆alkyl,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino,        N—(C₁₋₆alkyl)carbonylamino, phenyl, phenyl C₁₋₆ alkyl, carboxy,        C₁₋₆alkoxycarbonyl, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,        or N,N-di(C₁₋₆alkyl)amino,    -   —C(O)—R²⁰    -   wherein    -   R²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino,        or a 5-7 membered saturated or unsaturated heterocyclic ring        having 1 to 3 heteroatoms selected from the group consisting O,        S and N, and optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy,        oxo, amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆        acyl)amino, phenyl, or benzyl,    -   C₁₋₆ alkyl optionally substituted by R²¹    -   or    -   C₁₋₆ alkoxy optionally substituted by R²¹    -   wherein    -   R²¹ represents cyano, mono-, di or tri- halogen, hydroxy, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆        alkyl) amino, N-(halophenylC₁₋₆ alkyl) amino, amino C₂₋₆        alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹,        —NHC(O)—R²⁰¹, C₃₋₈cycloalkyl, isoindolino, phthalimidyl,        2-oxo-1,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or        unsaturated heterocyclic ring having 1 to 4 heteroatoms selected        from the group consisting O, S and N optionally substituted by        -   hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,            hydroxyC₁₋₆ alkoxy, oxo, amino, aminoC₁₋₆alkyl,            N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆            acyl)amino, or benzyl,        -   wherein        -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆ alkyl) amino,            C₁₋₆alkyl, aminoC₁₋₆ alkyl, aminoC₂₋₆ alkylenyl, C₁₋₆            alkoxy, a 5 or 6 membered saturated or unsaturated            heterocyclic ring having 1 to 4 heteroatoms selected from            the group consisting O, S and N optionally substituted by            hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,            hydroxyC₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,            N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino or benzyl;    -   R³ represents hydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl        optionally substituted by aryl C₁₋₆ alkoxy or mono-, di- or tri-        halogen;    -   R⁴ represents hydrogen or C₁₋₆ alkyl;    -   R⁵ represents hydrogen or C₁₋₆ alkyl; and    -   R⁶ represents halogen, hydrogen or C₁₋₆ alkyl.

The compounds of the present invention show PI3K inhibitory activity andPI3K-γ inhibitory activity. They are, therefore, suitable for theproduction of medicament or medical composition, which may be useful fortreatment and prophylaxis of PI3K and/or PI3K-γ related diseases forexample, inflammatory and immunoregulatory disorders, such as asthma,atopic dermatitis, rhinitis, allergic diseases, chronic obstructivepulmonary disease (COPD), septic shock, joint diseases, autoimmunepathologies such as rheumatoid arthritis, and Graves' disease,myocardial contractility disorders, heart failure, thromboembolism,ischemia, cardiac hypertrophy, atherosclerosis and cancer such as skincancer, bladder cancer, breast cancer, uterus cancer, ovary cancer,prostate cancer, lung cancer, colon cancer, pancreas cancer, renalcancer, gastric cancer, brain tumor, leukemia, etc.

The compounds of the present invention are also useful for treatment ofpulmonary hypertension, renal failure, Huntington's chorea and cardiachypertrophy, as well as neurodegenerative disorders such as Parkinson'sdisease, Alzheimer's disease, diabetes and focal ischemia, since thediseases also relate to PI3K activity in a human or animal subject.

This invention is also to provide a method for treating or preventing adisorder or disease associated with PI3K activity, especially withPI3K-γ activity, in a human or animal subject, comprising administeringto said subject a therapeutically effective amount of the fusedazolepyrimidine derivatives shown in the formula (I), its tautomeric orstereoisomeric form, or a physiologically acceptable salt thereof.

Further this invention is to provide a use of the fused azolepyrimidinederivatives shown in the formula (I), its tautomeric or stereoisomericform, or a physiologically acceptable salt thereof in the preparation ofa medicament.

In one embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof; wherein

-   X represents CR⁵R⁶ or NH;-   Y¹ represents CR³ or N;-   Chemical bond between Y²═Y³ represents a single bond or double bond,    with the proviso that when the Y²═Y³ represents a double bond,-   Y² and Y³ independently represent CR⁴ or N, and-   when Y²═Y³ represents a single bond, Y² and Y³ independently    represent CR³R⁴ or NR⁴;-   Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N;-   R¹ represents    -   C₁₋₆ alkyl optionally substituted by    -   mono-, di- or tri- halogen, phenyl, methoxyphenyl, phenoxy, or        thienyl,    -   C₁₋₆ alkoxy optionally substituted by mono-, di- or tri-        halogen, phenyl, methoxyphenyl, phenoxy, or thienyl,    -   or    -   one of the following carbocyclic and heterocyclic rings selected        from the group consisting of cyclopropyl, cyclohexyl,        piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, full, thienyl,        thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,        isoimidazolyl, pyrazolyl, 1,2,3-thiadiazolyl,        1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,        1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,        1,3,4-oxadiazolyl, 1,2,3-triazole, 1,2,4-triazole,        1,2,5-triazole, 1,3,4-triazole, phenyl, pyridyl, pyrazinyl,        pyrimidinyl, pyridazinyl, 1-benzothiophenyl, benzothiazolyl,        benzimidazolyl, 3H-imidazo[4,5-b]pyridinyl, benzotriazolyl,        indolyl, indazolyl, imidazo[1,2-a]pyridinyl, quinolinyl, and        1,8-naphthyridinyl,    -   wherein    -   said carbocyclic and heterocyclic rings optionally substituted        with 1 to 3 substituents selected from the group consisting of        hydroxy, halogen, nitro, cyano, carboxy, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,        N—(C₁₋₆alkoxycarbonyl)amino, N-(formyl)-N—(C₁₋₆alkyl)amino,        N[N,N-di(C₁₋₆alkyl)amino methylene]amino,        N[N,N-di(C₁₋₆alkyl)amino (C₁₋₆alkylene)methylene]amino,        N—[N,N-di(C₁₋₆alkyl)amino C₂₋₆alkenyl]amino, C₁₋₆ alkylthio,        C₁₋₆alkanesulfonyl, sulfamoyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl,        pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyridyl, phenyl        C₁₋₆alkoxycarbonyl,    -   thiazolyl optionally substituted by    -   pyridyl,    -   piperazinyl optionally substituted by C₁₋₆ alkyl or C₁₋₆alkoxy    -   and    -   C₁₋₆alkyl optionally substituted by mono-, di- or tri- halogen;-   R² represents hydroxy, halogen, nitro, cyano, carboxy, amino,    N—(C₁₋₆alkyl)amino, N-(hydroxy C₁₋₆alkyl)amino,    N,N-di(C₁₋₆alkyl)amino, N-(hydroxy C₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,    C₂₋₆alkenyl, C₁₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆acyloxy,    aminoC₁₋₆ acyloxy, furyl, morpholino, phenyl, piperidino, aryl,    -   pyrrolidinyl optionally substituted by C₁₋₆acylamino,    -   piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,        carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or        N,N-di(C₁₋₆alkyl)aminocarbonyl,    -   piperazinyl optionally substituted by C₁₋₆ alkyl,    -   C₁₋₆ alkyl optionally substituted by cyano, mono-, di- or tri-        halogen, hydroxy, amino, N—(C₁₋₆alkyl)amino, N-(hydroxy        C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, C₃₋₆ cycloalkyl,        tetrazolyl, tetrahydropyranyl, morpholino, phthalimidyl,        2-oxo-1,3oxazolidinyl, phenyl,    -   —C(O)—R²⁰¹,    -   pyrrolidinyl optionally substituted by C₁₋₆acylamino,    -   piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,        carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or        N,N-di(C₁₋₆alkyl)aminocarbonyl,    -   or    -   piperazinyl optionally substituted by C₁₋₆ alkyl,    -   wherein    -   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,        N,N-di(C₁₋₆alkyl)amino, N-halobenzyl)amino, C₁₋₆alkyl, C₁₋₆        alkoxy, tetrazolyl, tetrahydropyranyl, morpholino, pyrrolidinyl        optionally substituted by C₁₋₆acylamino,    -   piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,        carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or        N,N-di(C₁₋₆alkyl)aminocarbonyl,    -   or    -   piperazinyl optionally substituted by C₁₋₆ alkyl,    -   C₁₋₆ alkoxy optionally substituted by cyano, mono-, di- or tri-        halogen, hydroxy, C₁₋₆alkoxy, hydroxy C₁₋₆ alkoxy, amino,        N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, pyrrolyl,        tetrazolyl, tetrahydropyranyl, morpholino, phthalimidyl,        2-oxo-1,3oxazolidinyl, phenyl, —C(O)—R²⁰¹,    -   pyrrolidinyl optionally substituted by C₁₋₆acylamino,    -   piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,        carboxy, aminocarbonyl, N—(C₁₋₆-alkyl)aminocarbonyl, or        N,N-di(C₁₋₆-alkyl)aminocarbonyl,    -   or p1 piperazinyl optionally substituted by C₁₋₆ alkyl,    -   wherein-   R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,    N,N-di(C₁₋₆alkyl)amino, N(halobenzyl)amino, C₁₋₆ alkyl, C₁₋₆ alkoxy,    amino C₂₋₆ alkylenyl, tetrazolyl, tetrahydropyranyl, morpholino,    -   pyrrolidinyl optionally substituted by C₁₋₆acylamino,    -   piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,        carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, or        N,N-di(C₁₋₆alkyl)aminocarbonyl,    -   or    -   piperazinyl optionally substituted by C₁₋₆alkyl;-   R³ represents hydrogen, halogen, C₁₋₆ alkyl optionally substituted    by aminocarbonyl, arylC₁₋₆ alkoxy, or mono-, di- or tri-halogen;-   R⁴ represents hydrogen or C₁₋₆ alkyl;-   R⁵ represents hydrogen or C₁₋₆ alkyl; and-   R⁶ represents hydrogen, halogen or C₁₋₆ alkyl.

In another embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof: wherein

-   X represents CR⁵R⁶ or NH;-   Y¹ represents N;-   Y² and Y³ represent CR³R⁴;-   Chemical bond between Y²═Y³ represents a single bond-   Z⁴ represents CH;-   Z¹, Z² and Z³ independently represent N, CH or CR²;-   R¹ represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl,    3-furyl, imidazolyl, pyrimidinyl, pyridazinyl, piperazinyl,    1,2,3-thiadiazolyl, 1,3-benzothiazolyl, quinolyl,    3H-imidazo[4,5-b]pyridinyl, 1H-pyrrol-2-yl optionally substituted by    C₁₋₆alkyl,    -   1H-pyrrol-3-yl optionally substituted by C₁₋₆alkyl, pyrazolyl        optionally substituted by 1 or 2 C₁₋₆alkyl, isoxazolyl        optionally substituted by 1 or 2 C₁₋₆alkyl,    -   2-thienyl optionally substituted by chloro, nitro, cyano, or        C₁₋₆ alkyl,    -   3-thienyl optionally substituted by chloro, nitro, cyano, or        C₁₋₆ alkyl,    -   piperidinyl optionally substituted by C₁₋₆alkoxycarbonyl, or        benzyloxycarbonyl,    -   phenyl optionally substituted by 1 to 3 substituents selected        from the group consisting of fluoro, chloro, hydroxy, nitro,        cyano, carboxy, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl,        amino, N—(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,        N—(C₁₋₆alkoxycarbonyl)amino, N,N-di(C₁₋₆alkyl)amino,        N-(formyl)-N—C₁₋₆alkyl amino, C₁₋₆ alkylthio,        C₁₋₆alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl,        and piperazinyl optionally substituted by C₁₋₆alkyl,    -   pyridyl optionally substituted by 1 or 2 substituents selected        from the group consisting of chloro, hydroxy, carboxy,        C₁₋₆alkoxy, C₁₋₆alkylthio, amino, N—(C₁₋₆alkyl)amino,        N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,        N—(C₁₋₆acyl)amino, N—(C₁₋₆alkane)sulfonyl amino,        N[N,N-di(C₁₋₆alkyl)amino methylene]amino, and C₁₋₆alkyl        optionally substituted by tri halogen,    -   pyrazinyl optionally substituted by C₁₋₆alkyl,    -   1,3-thiazolyl optionally substituted by 1 or 2 substituents        selected from the group consisting of C₁₋₆alkyl, pyridyl and        N—(C₁₋₆alkoxycarbonyl)amino, indolyl optionally substituted by        C₁₋₆alkyl,    -   benzimidazolyl optionally substituted by C₁₋₆alkyl or tri-halo        C₁₋₆alkyl,    -   1,2,3-benzotriazolyl optionally substituted by C₁₋₆alkyl,        1,8-naphthyridinyl optionally substituted by    -   C₁₋₆alkyl optionally substituted by tri halogen,    -   C₁₋₆ alkyl optionally substituted by tri-halogen, phenyl,        phenoxy, or thienyl,    -   or    -   C₁₋₆alkoxy optionally substituted by phenyl, phenoxy, or        thienyl;    -   R² represents fluoro, chloro, bromo, hydroxy, nitro, vinyl,        cyano, amino, aminoacetoxy, N—(C₁₋₆alkyl)amino,        N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,        2-furyl, piperidino, morpholino, phenyl,        -   pyrrolidinyl optionally substituted by acetamido,        -   piperidino optionally substituted by hydroxy,        -   piperazinyl optionally substituted by methyl, benzyl,            C₁₋₆alkoxycarbonyl, or aminocarbonyl,        -   C₁₋₆ alkyl optionally substituted by cyano, tri-fluoro,            carboxy, methoxycarbonyl, aminocarbonyl,            tert-butoxycarbonyl, tetrahydropyranyl, or morpholino,        -   C₁₋₆ alkoxy optionally substituted by hydroxy, cyano,            methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy,            aminoacetyl, dimethylamino, aminocarbonyl,            methylaminocarbonyl, dimethylaminocarbonyl,            isopropylaminocarbonyl, fluorobenzylaminocarbonyl,            cyclopropyl, pyrrolidinyl, piperidino, tetrahydropyranyl,            morpholino, morpholinocarbonyl, 2-oxo-1,3-oxazolidin-4-yl,            phthalimid-N-yl, or hydroxy C₁₋₆ alkyleneoxy,    -   R³ represents hydrogen;    -   R⁴ represents hydrogen;    -   R⁵ represents hydrogen; and    -   R⁶ represents hydrogen.

In another embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof:

-   X represents CR⁵R⁶ or NH;-   Y¹ represents N;-   Y² and Y³ represent CR³R⁴;-   Chemical bond between Y²═Y³ represents a single bond-   Z³ and Z⁴ represent CH;-   Z¹ and Z² independently represent CH or CR²;-   R¹ represents 3H-imidazo[4,5-b]pyridinyl, benzimidazolyl pyridyl    optionally substituted by hydroxy, amino, acetamido,    methoxybenzyloxy or methylsulfonylamino,    -   or    -   1,3-thiazolyl optionally substituted by 1 or 2 methyl;-   R² represents fluoro, chloro, bromo, morpholino, piperazinyl,    methylpeperazinyl, methyl, tri-fluoro methyl, or    -   C₁₋₆ alkoxy optionally substituted by hydroxy, cyano, carboxy,        dimethylaminocarbonyl, tetrahydropyranyl, morpholino,        morpholinocarbonyl, tetrazolyl, or phthalimid-N-yl;    -   R³ represents hydrogen;    -   R⁴ represents hydrogen;    -   R⁵ represents hydrogen; and    -   R⁶ represents hydrogen.

In another embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof:

wherein

-   X represents CR⁵R⁶ or NH;-   Y¹ represents N;-   Y² and Y³ represent CR³R⁴;-   Chemical bond between Y²═Y³ represents a single bond.-   Z³ and Z⁴ represent CH;-   Z¹ and Z² independently represent CH or CR²;

In another embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof:

-   X represents CR⁵R⁶ or NH;-   Y¹ represents N;-   Y² and Y³ represent CR³R⁴;-   Chemical bond between Y²═Y³ represents a single bond-   Z¹ and Z⁴ represent CH;-   Z² and Z³ independently represent CH or CR²;

In another embodiment, the present invention provides the fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof:

-   X represents CR⁵R⁶or NH;-   Y¹ represents N;-   Y² and Y³ represent CR³R⁴;-   Chemical bond between Y²═Y³ represents a single bond;-   Z¹, Z³ and Z⁴ represent CH;-   Z² represents CR²;

The preferable compounds of the present invention are as follows:

-   -   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-yl-ethylenol;    -   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-{5-2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxy-vinyl]pyridin-2-yl}acetamide;    -   2-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)-N,N-dimethylacetamide;    -   2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;    -   2-[8-(2-hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;    -   ({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetic        acid;    -   4-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)butanoic        acid;    -   ({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetonitrile;    -   2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;    -   2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;    -   5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-3-ol;    -   N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;    -   6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;    -   5-hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy]nicotinamide;    -   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;    -   5-hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;    -   N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;    -   N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;    -   2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethylenol;    -   N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;    -   N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   6-(acetamido)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;    -   N-{5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-2-yl}acetamide;    -   6-methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;    -   1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]ethylenol;    -   N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;    -   N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;    -   N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;    -   N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;    -   N-{5-[2-(7,9dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;    -   N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;        and    -   2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;    -   and its tautomeric or stereoisomeric form, pharmaceutically        acceptable salts thereof.

Further, the present invention provides a medicament, which includes oneof the compounds, described above and optionally pharmaceuticallyacceptable excipients.

Alkyl per se and “alk” and “alkyl” in alkane, alkoxy, alkanoyl,alkylamino, alkylaminocarbonyl, alkylaminosulphonyl,alkylsulphonylamino, alkoxycarbonyl, alkoxycarbonylamino andalkanoylamino represent a linear or branched alkyl radical havinggenerally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3carbon atoms, representing illustratively and preferably methyl, ethyl,propyl, isopropyl, isobutyl, tert-butyl, sec-butyl, pentyl, n-hexyl, andthe like.

Alkylene represents the divalent linear or branched saturatedhydrocarbon radical, consisting solely of carbon and hydrogen atoms,having generally 1 to 6 carbon preferably 1 to 4 and particularlypreferably 1 to 3 carbon atoms, representing illustratively andpreferably methylene, ethylene, 2-methyl-propylene, butylene,2-ethylbutylene and the like.

Alkoxy illustratively and preferably represents methoxy, ethoxy,n-propoxy, iso-propoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.

Alkylamino represents an alkylamino radical having one or two(independently selected) alkyl substituents, illustratively andpreferably representing methylamino, ethylamino, n-propylamino,isopropylamino, tert-butylamino, n-pentylamino, n-hexyl-amino,N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino,N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino,N-n-hexyl-N-methylamino and the like.

Alkylamninocarbonyl represents an radical having one or two(independently selected) alkyl substituents, illustratively andpreferably representing methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylamino-carbonyl,tert-butyl-aminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl,N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl,N-isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl,N-ethyl-N-n-pentylamino-carbonyl, N-n-hexyl-N-methylaminocarbonyl andthe like.

Alkylaminosulphonyl represents an alkylaminosulphonyl radical having oneor two (independently selected) alkyl substituents, illustratively andpreferably representing methylaminosulphonyl, ethylaminosulphonyl,n-propylaminosulphonyl, isopropylaminosulphonyl,tert-butylaminosulphonyl, n-pentylaminosulphonyl,n-hexyl-aminosulphonyl, N,N-diimethylaminosulphonyl,N,N-diethylaminosulphonyl, N-ethyl-N-methylamino-sulphonyl,N-methyl-N-n-propylaminosulphonyl, N-isopropyl-N-n-propylaminosulphonyl,N-t-butyl-N-methylaminosulphonyl, N-ethyl-N-n-pentylaminosulphonyl,N-n-hexyl-N-methylaminosulphonyl and the like.

Alkylsulphonyl illustratively and preferably represents methylsulphonyl,ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,tert-butyl-sulphonyl, n-pentyl-sulphonyl, n-hexylsulphonyl and the like.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl, n-hexoxycarbonyl and the like.

Alkoxycarbonylamino illustratively and preferably representsmethoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,isopropoxycarbonylamino, tert-butoxycarbonylamino,n-pentoxycarbonylamino, n-hexoxycarbonylamino and the like.

Alkanoylamino illustratively and preferably represents acetamido,ethylcarbonylamino and the like.

Cycloalkyl per se and in cycloalkylamino and in cycloalkylcarbonylrepresents a cycloalkyl group having generally 3 to 8 and preferably 5to 7 carbon atoms, illustratively and preferably representingcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike.

Aryl per se and “aryl” in arylamino, arylcarbonyl, alkoxyaryl,represents a mono- to tricyclic aromatic carbocyclic radical havinggenerally 6 to 14 carbon atoms, illustratively and preferablyrepresenting phenyl, naphthyl, phenanthrenyl and the like.

Arylamino represents an arylamino radical having one or two(independently selected) aryl substituents, illustratively andpreferably representing phenylamino, diphenylamino naphthylamino and thelike.

Heteroaryl per se and “heteroaryl” in heteroarylamino andheteroarylcarbonyl represents an aromatic mono- or bicyclic radicalhaving generally 5 to 15 and preferably 5 or 6 ring atoms and up to 5and preferably up to 4 hetero atoms selected from the group consistingof S, O and N, illustratively and preferably representing thienyl,furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiazolyl, pyrazinyl,pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, indolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, 1,3benzodioxole, benzofuranyl, benzofuran-2,5-diyl, benzofuran-3,5-diyl,and the like.

Heterocyclic per se and heterocyclic ring per se represent a mono- orpolycyclic, preferably mono- or bicyclic, nonaromatic heterocyclicradical having generally 4 to 10 and preferably 5 to 8 ring atoms and upto 3 and preferably up to 2 hetero atoms and/or hetero groups selectedfrom the group consisting of N, O, S, SO and SO₂. The heterocyclylradicals can be saturated or partially unsaturated. Preference is givento 5- to 8-membered monocyclic saturated heterocyclyl radicals having upto two hetero atoms selected from the group consisting of O, N and S,such as illustratively and preferably tetrahydrofuran-2-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholino,perhydroazepinyl.

Heterocyclylcarbonyl illustratively and preferably representstetrahydrofuran-2-carbonyl, pyrrolidine-2-carbonyl,pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl,morpholinecarbonyl, perhydroazepinecarbonyl.

Halogen and Halo represents fluoro, chloro, bromo and/or iodo.

Further, the present invention provides a medicament which include oneof the compounds described above and optionally pharmaceuticallyacceptable excipients.

EMBODIMENT OF INVENTION

The compound of the formula (I) of the present invention can be, but notlimited to be, prepared by reactions described below. In someembodiments, one or more of the substituents, such as amino group,carboxyl group, and hydroxyl group of the compounds used as startingmaterials or intermediates are advantageously protected by a protectinggroup known to those skilled in the art. Examples of the protectinggroups are described in “Protective Groups in Organic Synthesis (3^(nd)Edition)” by Greene and Wuts.

The compound of the formula (I) of the present invention can be, but notlimited to be, prepared by the Method [A], and [B] below.

The compound of the formula (I-a):

(wherein R¹, R⁵, R⁶, Y¹, Y², Y³, Z¹, Z², Z³ and Z⁴ are the same asdefined above) can be, but not limited to be, prepared by the followingMethod A.

The compound of formula (I-a) can be prepared, for example, by thereaction of the compound of formula (II) (wherein Y¹, Y², Y³, Z¹, Z², Z³and Z⁴ are the same as defined above) with a compound of formula (III)(wherein R¹, R⁵ and R⁶ are the same as defined above, and L representsC₁₋₆ alkyl).

The reaction may be carried out without solvent, or in a solventincluding, for instance, ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; amides such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide andN-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO);alcohols such as methanol, ethanol, 1-propanol, isopropanol andtert-butanol; water, and others. Optionally, two or more of the solventsselected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 10° C. to 200° C. and preferably about 50° C. to 160°C. The reaction may be conducted for, usually, 10 minutes to 48 hoursand preferably 30 minutes to 24 hours.

Preparation of the Intermediates

The compound of formula (II′) (wherein Y¹, Z¹, Z², Z³ and Z⁴ are thesame as defined above, Y² and Y³ independently represent CR³R⁴ or NR⁴and are connected by single bond) and the compound of formula (II″)(wherein Y¹, Z¹, Z², Z³ and Z⁴ are the same as defined above, Y² and Y³independently represent CH or N and are connected by double bond) canbe, but not limited to be, prepared by the following Method [A-i].

In the step 1, the compound of formula (II′) (wherein Y¹, Z¹, Z², Z³ andZ⁴ are the same as defined above, Y² and Y³ independently representCR³R⁴ or NR⁴ and are connected by single bond) can be prepared, forexample, by the reaction of the compound of formula (VI) (wherein Z¹,Z², Z³ and Z⁴ are the same as defined above) with an diaminoalkanederivatives such as ethylenediamine.

The reaction can be advantageously carried out using appropriatedehydrating agents such as SOCl₂, POCl₃, P₂O₅, P₂S₅, CS₂ and others.

The reaction may be carried out without solvent, or in a solventincluding for instance, ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene and others. Optionally,two or more of the solvents selected from the listed above can be mixedand used.

The reaction temperature is usually, but not limited to, about 10° C. to200° C. and preferably about 50° C. to 200° C. The reaction may beconducted for, usually, 10 minutes to 48 hours and preferably 30 minutesto 24 hours.

In the step 2, the compound of formula (II″) (wherein Y¹, Z¹, Z², Z³ andZ⁴ are the same as defined above, Y² and Y³ independently represent CHor N and are connected by double bond) can be prepared, for example,from the compound of formula (II′) (wherein Y¹, Z¹, Z², Z³ and Z⁴ arethe same as defined above, Y² and Y³ independently represent CR³R⁴ orNR⁴ and are connected by single bond) by the oxidation reaction using anagent such as MnO₂, KMnO₄ and others, or by the dehydrogenation reactionusing palladium on carbon.

The reaction can be carried out in a solvent including, for instance,ethers such as diethyl ether, isopropyl ether, dioxane andtetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbonssuch as benzene, toluene and xylene; dimethylformamide (DMF),dimethylacetamide(DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), andothers. Optionally, two or more of the solvents selected from the listedabove can be mixed and used.

The reaction temperature is usually, but not limited to, about 0° C. to200° C. and preferably about 50° C. to 200° C. The reaction may beconducted for, usually, 30 minutes to 48 hours and preferably 2 hours to24 hours.

The compound of formula (VI) is commercially available or can besynthesized by conventional method.

The compound of formula (III) can be prepared, for example, by thefollowing Method [A-ii].

The compound of formula (III) (wherein L, R¹, R⁵ and R⁶ are the same asdefined above) can be prepared by the reaction of the compound offormula (VII) (wherein R¹, R⁵ and R⁶ are the same as defined above) withthe compound of formula (VIII) (wherein L is the same as defined above)in the presence of a base such as potassium hydride, potassiumhexamethyldisilazide, and others.

The reaction can be carried out in a solvent including, for instance,ethers such as diethyl ether, isopropyl ether, dioxane andtetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbonssuch as benzene, toluene and xylene, dimethylformamide (DMF),dimethylacetamide(DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), andothers. Optionally, two or more of the solvents selected from the listedabove can be mixed and used.

The reaction temperature is usually, but not limited to, about −100° C.to 100° C. The reaction may be conducted for, usually, 30 minutes to 48hours and preferably 2 hours to 12 hours.

Alternatively, the compound of formula (III) can be prepared, forexample, by the following Method [A-iii].

The compound of formula (II) (wherein L, R¹, R⁵ and R⁶ are the same asdefined above) can be prepared by the reaction of the compound offormula (IX) (wherein R¹ is the same as defined above and L′ is aleaving group such as halogen atom e.g., chlorine or bromine atom, orimidazole) with the compound of formula (X) (wherein wherein L, R⁵ andR⁶ are the same as defined above) or its salts, for example, potassiumsalt.

The reaction can be carried out in the presence of Lewis acid includingmagnesium salts, such as magnesium bromide, magnesium chloride,magnesium iodide, magnesium acetate, and others or a base such asn-butyl lithium, sec-butyl lithium, and others. The reaction can becarried out in a solvent including, for instance, ethers such as diethylether, isopropyl ether, dioxane and tetrahydrofuran (THF) and1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene andxylene, and others. Optionally, two or more of the solvents selectedfrom the listed above can be mixed and used.

The preparation of the compound formula ([-b):

(wherein R¹, Y¹, Y², Y³, Z¹, Z², Z³ and Z⁴ are the same as definedabove) can be, but not limited to be, prepared by the following MethodB.

The compound of formula (I-b) can be prepared, for example, by thereaction of the compound of formula (IV) (wherein Y¹, Y², Y³, Z¹, Z², Z³and Z⁴ are the same as defined above) with a compound of formula (V)(wherein R¹ is the same as defined above and L″ is a leaving group, suchas hydroxy; halogen atom e.g., chlorine, bromine, or iodine

atom; imidazole or,

wherein R¹ is the same as defined above). In the case L″ is hydroxy, thereaction can be advantageously carried out by using a coupling agentsuch as benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP), 1,1′-carbonyldi(1,3-imiazole)(CDI),1,1′-carbonyldi(1,2,4-triazole)(CDT) and others.

In the case L″ is halogen atom, imidazole, or

the reaction can be advantageously conducted in the presence of a base,including, for instance, such as pyridine, triethylamine andN,N-diisopropylethylamine, dimethylaniline, diethylaniline, and others.

The reaction may be carried out without solovent, or in a solventincluding, for instance, ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about 40° C. to200° C. and preferably about 20° C. to 180° C. The reaction may beconducted for, usually, 30 minutes to 48 hours and preferably 2 hours to12 hours.

Preparation of Intermediates

The compound of formula (IV) can be, but not limited to be, prepared bythe following Method [B-i]:

The compound of formula (IV) (wherein Y¹, Y², Y³, Z¹, Z², Z³ and Z⁴ arethe same as defined above) can be prepared by the reaction of compoundof formula (II) (wherein Y¹, Y², Y³, Z¹, Z², Z³ and Z⁴ are the same asdefined above) with cyanogen halides such as cyanogen bromide.

The reaction may be carried out in a solvent including, for instance,ethers such as diethyl ether, isopropyl ether, dioxane andtetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbonssuch as benzene, toluene and xylene; amides such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide andN-methylpyrrolidone; alcohols such as methanol, ethanol, 1-propanol,isopropanol and tert-butanol; and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about −10+ C.to 200° C. The reaction may be conducted for, usually, 30 minutes to 48hours and preferably 1 hour to 24 hours.

The compound of formula (II) (wherein Y¹, Y², Y³, Z¹, Z², Z³ and Z⁴ anare the same as defined above) can be obtained in the same mannerdescribed in Method [A-i].

The compound of formula (VII), (VIII), (IX) and (X) are commerciallyavailable or can be synthesized by conventional method.

When the compound shown by the formula (I) or a salt thereof has anasymmetric carbon(s) in the structure, their optically active compoundsand racemic mixtures are also included in the scope of the presentinvention.

Typical salts of the compound shown by the formula (I) include saltsprepared by the reaction of the compound of the present invention with amineral or organic acid, or an organic or inorganic base. Such salts areknown as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as,without limitation, sulfuric acid, phosphoric acid, hydrochloric acid,hydrobromic acid, hydroiodic acid and the like, and organic acids, suchas, without limitation, p-toluenesulfonic acid, methanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as,without limitation, ammonium hydroxide, alkaline metal hydroxide,alkaline earth metal hydroxides, carbonates, bicarbonates, and the like,and organic bases, such as, without limitation, ethanolamine,triethylamine, tri(hydroxymethyl)aminomethane, and the like. Examples ofinorganic bases include, sodium hydroxide, potassium hydroxide,potassium carbonate, sodium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salts thereof, depending onits substituents, may be modified to form lower alkylesters or knownother esters; and/or hydrates or other solvates. Those esters, hydrates,and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms,such as, without limitation normal and enteric coated tablets, capsules,pills, powders, granules, elixirs, tinctures, solution, suspensions,syrups, solid and liquid aerosols and emulsions. They may also beadministered in parenteral forms, such as, without limitation,intravenous, intraperitoneal, subcutaneous, intramuscular, and the likeforms, well-known to those of ordinary skill in the pharmaceutical arts.The compounds of the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal delivery systems well-known to those ofordinary skilled in the art.

The dosage regimen with the use of the compounds of the presentinvention is selected by one of ordinary skill in the arts, in view of avariety of factors, including, without limitation, age, weight, sex, andmedical condition of the recipient, the severity of the condition to betreated, the route of administration, the level of metabolic andexcretory function of the recipient, the dosage form employed, theparticular compound and salt thereof employed.

The compounds of the present invention are preferably formulated priorto administration together with one or more pharmaceutically-acceptableexcipients. Excipients are inert substances such as, without limitationcarriers, diluents, flavoring agents, sweeteners, lubricants,solubilizers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Yet another embodiment of the present invention is pharmaceuticalformulation comprising a compound of the invention and one or morepharmaceutically-acceptable excipients that are compatible with theother ingredients of the formulation and not deleterious to therecipient thereof. Pharmaceutical formulations of the invention areprepared by combining a therapeutically effective amount of thecompounds of the invention together with one or morepharmaceutically-acceptable excipients. In making the compositions ofthe present invention, the active ingredient may be mixed with adiluent, or enclosed within a carrier, which may be in the form of acapsule, sachet, paper, or other container. The carrier may serve as adiluent, which may be solid, semi-solid, or liquid material which actsas a vehicle, or can be in the form of tablets, pills, powders,lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols,ointments, containing, for example, up to 10% by weight of the activecompound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with anoral, and non-toxic, pharmaceutically-acceptable carrier, such as,without limitation, lactose, starch, sucrose, glucose, sodium carbonate,mannitol, sorbitol, calcium carbonate, calcium phosphate, calciumsulfate, methyl cellulose, and the like; together with, optionally,disintegrating agents, such as, without limitation, maize, starch,methyl cellulose, agar bentonite, xanthan gum, alginic acid, and thelike; and optionally, binding agents, for example, without limitation,gelatin, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic guns, acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is inadmixture with the finely divided active ingredient. The activeingredient may be mixed with a carrier having binding properties insuitable proportions and compacted in the shape and size desired toproduce tablets. The powders and tablets preferably contain from about 1to about 99 weight percent of the active ingredient which is the novelcomposition of the present invention. Suitable solid carriers aremagnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and a sterileorganic solvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physicallydiscrete unit containing a unit dose, suitable for administration inhuman or other mammals. A unit dosage form can be a capsule or tablets,or a number of capsules or tablets. A “unit dose” is a predeterminedquantity of the active compound of the present invention, calculated toproduce the desired therapeutic effect, in association with one or moreexcipients. The quantity of active ingredient in a unit dose may bevaried or adjusted from about 0.1 to about 1000 milligrams or moreaccording to the particular treatment involved.

Typical oral dosages of the present invention, when used for theindicated effects, will range from about 0.01 mg/kg/day to about 100mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and mostpreferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In case ofparenteral administration, it has generally proven advantageous toadminister quantities of about 0.001 to 100 mg/kg/day, preferably from0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present inventionmay be administered in a single daily dose, or the total daily dose maybe administered in divided doses, two, three, or more times per day.Where delivery is via transdermal forms, of course, administration iscontinuous.

EXAMPLES

The present invention will be described in detail below in the form ofexamples, but they should by no means be construed as defining the metesand bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise,relate to percentages by weight.

¹H NMR spectra were recorded using either Bruker DRX-300 (300 MHz for¹H) spectrometer or Brucker 500 UltraShieled™ (500 MHz for 1H). Chemicalshifts are reported in parts per million (ppm) with tetramethylsilane(TMS) as an internal standard at zero ppm. Coupling constant (J) aregiven in hertz and the abbreviations s, d, t, q, m, and br refer tosinglet, doublet, triplet, quartet, multiplet, and broad, respectively.The mass determinations were carried out by MAT95 (Finnigan MAT).

Liquid Chromatography—Mass spectroscopy (LC-MS) data were recorded on aMicromass Platform LC with Shimadzu Phenomenex ODS column(4.6 mm φ×30mm) flushing a mixture of acetonitrile-water (9:1 to 1:9) at 1 ml/min ofthe flow rate. Mass spectra were obtained using electrospray (ES)ionization techniques (Micromass Platform LC). TLC was performed on aprecoated silica gel plate (Merck silica gel 60 F-254). Silica gel(WAKO-gel C-200 (75-150 μm)) was used for all column chromatographyseparations. All chemicals were reagent grade and were purchased fromSigma-Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyoCo., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridgeplc, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co., Ltd.

The effects of the compounds of the present invention were examined bythe following assays.

[Determination of IC50 Values of Compounds in Kinase Assay of PI3Kγ]

Chemicals and Assay Materials

Phosphatidylinositol (PtdIns) and phosphatidylserine (PtdSer) werepurchased from DOOSAN SERDARY RESEARCH LABORATORIES (Toronto, Canada).Recombinant human PI3Kγ (full length human PI3K p110γ fused with aHis₆-tag at the C-terminus expressed in S. frugiperda 9 insect cells)was obtained from ALEXIS BIOCHEMICALS (#201-055-C010; San Diego,Calif.). [γ³³P]ATP and unlabeled ATP were purchased from AMBRSHAMPHARMACIA BIOTECH (Buckinghamshire, UK) and ROCHE DIAGNOSTICS (Mannheim,Germany), respectively. Scintillation cocktails and MicroScint PS™ werepurchased from PACKARD (Meriden, Conn.). Maxisorp™ plates were purchasedfrom NALGE NUNC INTERNATIONAL K.K. (Tokyo, Japan). All other chemicalsnot further specified were from WAKO PURE CHEMICALS (Osaka, Japan).

Solid-Phase Lipid Kinase Assay

To assess inhibition of PI3Kγ by compounds, the Maxisorp™ plates werecoated with 50 μl/well of a solution containing 50 μg/ml PtdIns and 50μg/ml PtdSer dissolved in chloroform:ethanol (3:7). The plates weresubsequently air-dried by incubation for at least 2 hours in a fumehood. The reaction was set up by mixing 25 μl/well of assay buffer 2×(100 mM MOPSO/NaOH, 0.2 M NaCl, pH 7.0, 8 mM MgCl₂, 2 mg/ml BSA (fattyacid-free)) and 50 ng/well PI3Kγ in the lipid pre-coated plate and 10×test compounds were added in 2% DMSO. The reaction was started by adding20 μl/well of ATP mix (final 10 μM ATP; 0.05 μCi/well [γ³³P]ATP). Afterincubation at RT for 2 hours, the reaction was terminated by adding 50μl/well stop solution (50 mM EDTA, pH 8.0). The plate was then washedtwice with Tris-buffered saline (TBS, pH 7.4). MicroScint PS™ (PACKARD)scintillation mix was added at 100 μl/well, and radioactivity wascounted by using a TopCount™ (PACKARD) scintillation counter.

The inhibition percent at each concentration of compound was calculated,and IC50 values were determined from the inhibition of curve.

[Isozyme Selectivity Test in PI3K]

{Determination of IC50 Values of Compounds in Kinase Assay of PI3Kβ}

Recombinant baculovirus of PI3Kβ p110β and GST-p85α were obtained fromDr. Katada (University of Tokyo). Recombinant PI3K heterocomplex ofp110β and GST-p85α were co-expressed in insect cells according tomanufacture's instruction (Pharmingen, San Diego, Calif.), and purifiedwith glutathione affinity column. Kinase assay of PI3Kβ was prepared ina similar manner as described in the part of [Determination of IC50values of compounds in kinase assay of PI3Kγ].

[Selectivity Test with Other Kinases]

Kinase selectivity of the compounds was assessed by using a few kinaseassaies such as kinase assay of Syk.

{Syk Tyrosine Kinase Inhibitory Assay for Selectivity}

(1) Preparation of Syk Protein

A cDNA fragment encoding human Syk openreading frame was cloned fromtotal RNA of human Burkitt's lymphoma B cell lines, Raji (American TypeCulture Collection), with the use of RT-PCR method. The cDNA fragmentwas inserted into pAcG2T (Pharmingen, San Diego, Calif.) to construct abaculovirus transfer vector. Then the vector, together with thelinearized baculovirus (BaculoGold™, Pharmingen), was used to transfectSf21 cells (Invitrogen, San Diego, Calif.).

Generated recombinant baculovirus was cloned and amplified in Sf21cells. Sf21 cells were infected with this amplified high titer virus toproduce a chimeric protein of Syk kinase fused byglutathione-S-transferase (GST).

The resulting GST-Syk was purified with the use of glutathione column(Amersham Pharmacia Biotech AB, Uppsala, Sweden) according to themanufacturer's instruction. The purity of the protein was confirmed tobe more than 90% by SDS-PAGE.

(2) Synthesize of a Peptide

Next, a peptide fragment of 30 residues including two tyrosine residues,KISDFGLSKALRADENYYKAQTHGKWPVKW, was synthesized by a peptidesynthesizer. The N-terminal of the fragment was then biotinylated toobtain biotinylated activation loop peptide (AL).

(3) The Measurement of Syk Tyrosine Kinase Activity

All reagents were diluted with the Syk kinase assay buffer (50 mMTris-HCl (pH 8.0), 10 mM MgCl₂, 0.1 mM Na₃VO₄, 0.1% BSA, 1 mM DTT).First, a mixture (35 μl) including 3.2 μg of GST-Syk and 0.5 μg of ALwas put in each well in 96-well plates. Then 5 μl of a test compound inthe presence of 2.5% dimethyl sulfoxide (DMSO) was added to each well.To this mixture was added 300 μM ATP (10 μl) to initiate the kinasereaction. The final reaction mixture (50 μl) consists of 0.65 nMGST-Syk, 3 μM AL, 30 μM ATP, a test compound, 0.25% DMSO, and a Sykkinase assay buffer.

The mixture was incubated for 1 hour at room temperature (RT), and thereaction was terminated by the addition of 120 μl of termination buffer(50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 500 mM NaCl, 0.1% BSA). Themixture was transferred to streptavidin-coated plates and incubated for30 minutes. at room temperature to combine biotin-AL to the plates.After washing the plates with Tris-buffered saline (TBS) (50 mM Tris-HCl(pH 8.0), 138 mM NaCl, 2.7 mM KCl) containing 0.05% Tween-20 for 3times, 100 μl of antibody solution consisting of 50 mM Tris-HCl (pH8.0), 138 mM NaCl, 2.7 mM KCl, 1% BSA, 60 ng/ml anti-phosphotyrosinemono-clonal antibody, 4G10 (Upstate Biotechnology), which was labeledwith europium by Amersham Pharmacia's kit in advance, was added andincubated at room temperature for 60 minutes. After washing, 100 μl ofenhancement solution (Amersham Pharmacia Biotech) was added and thentime-resolved fluorescence was measured by multi-label counter ARVO(Wallac Oy, Finland) at 340 nm for excitation and 615 nm for emissionwith 400 msec of delay and 400 msec of window.

[Determination of IC50 Values of Compounds in Superoxide Generation fromHuman Peripheral Mononuclear Cells]

Blood (100 ml/donor) was taken from healthy human volunteers byvenepuncture with 50 ml syringes containing 50 units heparin. Red bloodcells were removed by incubation with 1% (w/v) dextran and 0.45% (w/v)glucose for 30 minutes at room temperature. After centrifugation at 350×g for 10 minutes, the cell pellet was resuspended in 10 ml PBS. The cellsuspension was gently layered on 20 ml of 60% and 20 ml of 80% Percoll(Amersham Pharmacia Biotech, Sweden) gradient in PBS in 50 ml tube(#2335-050, Iwaki, Japan). After centrifugation at 400× g for 30 minutesat room temperature, peripheral polymorphonuclear leukocytes (PMNs) wereobtained from the interference between 60% and 80% Percoll phases. Aftertwice washing in PBS, PMNs were suspended at a density of 10⁷ cells/mlin Hank's Balanced Salt Solution (HBSS: Nissui, Japan) supplemented by10 mM Na-Hepes (pH 7.6), 0.1% BSA and kept on ice until furter use.

To test inhibition of formyl-methionyl-leucyl-phenylalanine(fMLP)-induced superoxide generation by compounds, PMNs (2×10⁵cells/well) were seeded in HBSS, 10 mM Na-Hepes (pH 7.6), 0.1% BSA in96-well clear bottom black plate (Cat.#3904, Costar) and pretreated withluminol (1 μg/well; Sigma) and test compounds for 10 minutes at 37° C.fMLP peptide (Cat.#4066; Peptide Institute Inc, Japan) was prepared in10 μM in the same buffer and prepared in a polypropylene plate(Cat.#3365, Coster). Chemiluminescence (CL) was measured by FDSS-6000(Hamamatsu Photonics) over 15 minutes after stimulation with 1 μM fMLP.The percentage of inhibition at each concentration of compound wascalculated based on the first peak of CL at approximately 1 minute afteraddition of stimulus and IC50 values were determined from the inhibitioncurve.

For opsonized zymosan (OZ) and phorbol 12-myristate 13-acetate (PMA)stimulation, Zymosan A (Sigma) was suspended in HBSS at a concentrationof 1 mg/ml and incubated with human pooled serum at a finalconcentration range of 9 to 80% at 37° C. for 30 minutes to opsonize thezymosan, followed by centrifugation at 500× g for 10 minutes at 4° C.Then the sediments were washed twice in HBSS and finally resuspended inHBSS to a concentration between 1 and 10 mg/ml. Opsonized zymosan (OZ)was used at 5 mg/ml for stimulation. Phorboll2-myristate 13-acetate(PMA) was initially dissolved at a concentration of 0.1 mg/ml in DMSO asa stock solution and stored frozen at −20° C. PMA solution was preparedfrom the stock solution by further dilution in HBSS to the concentrationof 100 ng/ml. PMNs (2×10⁵ cells/well) were seeded in HBSS, 10 mMNa-Hepes (pH 7.6), 0.1% BSA in 96-well white plate (Packard) andpretreated with luminol (1 μg/well; Sigma) and test compounds for 10minutes at 37° C. CL was measured by Arvo counter (Wallac)) at 30minutes after the stimulation with OZ or PMA. The percentage ofinhibition at each concentration of compound was calculated and IC50values were determined from the inhibition curve.

[Determination of IC50 Values of Compounds in Elastase Release fromHuman Peripheral Mononuclear Cells]

To test inhibition of elastase release by compounds, PMNs (5×10⁵cells/well) were seeded in HBSS supplemented with 10 mM Na-Hepes (pH7.6), 0.1% 13SA in 96-well plate. Cells were pretreated withcytochalasine B (0.1 μg/well; Nakarai, Japan) and test compounds in 90μl/well for 10 minutes at 37° C. Cells were stimulated with 1 μM fMLPfor 15 minutes at 37° C. Supernatants (40 μl/well) were collected into384 well black plate (Packard) to measure elastase activity.Fluorescent-based elastase reaction was started by the addition of 10 μlof 0.5 mM Suc-Ala-Ala-Ala-MCA (Cat. #3133v; Peptide Institute Inc,Japan) into the 384 well plate at room temperature. The fluorescenceemission was measured at 460 nm (γex, 360 nm) by using a Wallac-Arvocounter (PerkinElmer, Boston, Mass.) fluorescence plate leader for 120minutes. IC50 values of compounds were determined at the initialvelocity of the reaction.

[Determination of IC50 Values of Compounds in Chemotaxis Assay with theUse of Human PMNs]

Freshly prepared PMNs (1.1×10⁷ cells/ml) were incubated with compoundsin a polypropylene 96 well plate (Cat.#3365, Coster) for 10 minutes inHBSS supplemented with 10 mM Na-Hepes (pH 7.6), 0.1% BSA. Cells (100 μl)were incubated with test compounds or vehicle for 30 minutes and weretransferred into an Multiwell insert (Cat.# 351183; Falcon) 24w plate.FMLP (10 nM, 0.5 ml) was added into the lower chamber of the plate, andchemotaxis was measured in CO₂ incubator at 37° C. for 1 hour. Migratedcells were counted using FACScan (Becton Dickinson, Franklin Lakes,N.J.). The percentage of inhibition at the each concentration ofcompound was calculated, and the IC50 values were determined from theinhibition curve.

[Determination of IC50 Values of Compounds in Chemotaxis Assay with theUse of Transfectants]

(1) Cell

Human CCR3-transformed L1.2 cells were used. Human CCR3-expressing L1.2stable transformant was established by electroporation, referring to themethods described in J. Exp. Med. 183:2437-2448, 1996. The humanCCR3-transformed L1.2 cells were maintained in RPMI-1640 supplementedwith 10% FCS, 100 units/ml of penicillin G and 100 μg/ml ofstreptomycin, and 0.4 mg/ml of Geneticin. One day before the chemotaxisassay, cells were pretreated with 5 mM sodium butyrate—containingculture medium (5×10⁵ cells/ml) for 20-24 hours to increase theexpression of CCR3.

(2) Chemotaxis Assay

Butyrate-pretreated cells were suspended in chemotaxis buffer (Hanks'solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% human serum albuminCat.#A-1887 Sigma) at a cell density of 1.1×10⁷ cells/ml. A mixture of90 μl of cell suspension and 10 μl of compound solution diluted withchemotaxis buffer (10-times concentration of the final concentration)were preincubated for 10 minutes at 37° C. The mixture of cells andcompounds was added into the upper chamber of the 24-well chemotaxischamber (Transwell™, Cat.#3421, Costar, pore size;5 μm). 0.5 ml of 10 nMof human recombinant eotaxin (Cat.#23209, Genzyme Techne) solution,diluted with chemotaxis buffer, was added into the lower chamber of thechemotaxis plate. Then, chemotaxis was performed in CO₂ incubator at 37°C. for 4 hours. After 4 hours incubation, migrated cells were countedusing FACScan (Becton Dickinson). The percentage of inhibition at theeach concentration of compound was calculated, and IC50 values weredetermined from the inhibition curve.

[Mouse fMLP-Induced Pleurisy Model]

Seven weeks old BALB/c female mice were divided into 3 groups, anontreatment group, a vehicle group and a treatment group. Mice in thetreated group were first injected intravenously with compounds of thepresent invention at varied doses. Mice in the vehicle group wereinjected with vehicle containing 10% Cremophor EL (Nacalai Tesque) insaline. Three minutes after the treatment, a solution containing 1mg/mouse of fMLP in 3.3% DMSO in PBS was administrated intrapleuralyinto a vehicle group and a treated group mice. Four hours afterfMLP-injection, mice were sacrificed and pleural fluid was collected bywashing the pleural cavity twice with 2 ml PBS. Total cells permilliliter of pleural fluid were counted using a hema-cytometer. Celldifferentiation of pleural fluid was determined by counting a minimum of200 cells from a Giemsa's-stained cytospin slide preparation.Statistical analysis was performed by means of Student's t-test forpaired data or analysis of variance with Dunnett's Post test , usingGraphPadPRISM for Windows, version 2.01.

For practical reasons, the compounds are grouped in some classes ofactivity as follows:

In vitro IC₅₀=A(= or <)0.1 μM<B(= or <)0.5 μM<C(= or <)2 μM<D

The compounds of the present invention also show strong activity in vivoassays.

(dec.) in the following tables represents decomposition.

Example 1-1Z)-2-(8,9-Dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol(1) Methyl 3-oxo-3-(3-pyridinyl)propanoate

A 0.5 M solution of pottasium hexamethyldisilazide in toluene (22 ml, 11mmol) was mixed with tetrahydrofuran (5 ml), and the mixture was cooledat −78° C. To the cold (−78° C.) mixture was added dropwise a solutionof 3-acethylpyridine (1.0 g, 8.26 mmol) in tetrahydrofuran (5 ml). Themixture was warmed to room temperature and stirred for 3 hours. Themixture was cold at −78° C., and then dimethyl carbonate (1.2 ml, 14.3mmol) was added dropwise. The resulting solution was allowed to warm toroom temperature and stirred overnight. The reaction solution wasquenched by adding aqueous 1N HCl solution, and extracted three timeswith ethyl acetate. The combined organic layers were washed with waterand brine, dried over magnesium sulfate, filtrated, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica-gel hexane/ethyl acetate, 1/1) to give methyl3-oxo-3-(3-pyridinyl)propanoate (1.0 g, 68% yield) as an oil.

(2) 2-(4,5-Dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline

2-Amino-4,5-dimethoxybenzonitrile (5.0 g, 28 mmol) was added toethylenediamine (7.9 g, 131 mmol) at room temperature. The resultingsolution was warmed to 40, and a catalitic amount of diphosphoruspentasulfide (50 mg) was added. The mixture was heated to 80-90, and thestirring was continued overnight. The reaction mixture was diluted withwater, and the resulting precipitate was collected by filtration to give2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (5.1 g, 82%) as asolid.

(3)(Z)-2-(8,9-Dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol

A mixture of 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (0.15g, 0.68 mmol) and methyl-3-oxo-3(3-pyridinyl)propanoate (0.20 g, 1.12mmol) was stirred at 155. for 1 hour. The reaction mixture was purifiedby column chromatography on silica-gel (dichloromethane/methanol, 25/1)to give(Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol (66.9 mg, 28%) as a yellow solid.

Melting point: 275° C.

Mass spectrometry: 351

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

¹H-NMR (500. MHz, DMSO-d6): d 3.79 (3H, s), 3.88 (3H, s), 3.98-4.08 (4H,m), 5.63 (1H, s), 7.13 (1H, s), 7.24 (1H, s), 7.50 (1H, dd, J=4.7, 7.8Hz), 8.27 (1H, dt, J=1.6, 7.8 Hz), 8.67 (1H, dd, J=1.6, 4.7 Hz), 9.13(1H, d, J=1.6 Hz), 13.9 (1H, bs).

Example 1-2(Z)-2-(8,9-Dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)-ethenolhydrochloride

To a solution of(Z-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenol(16.8 mg, 0.05 mmol)) in dioxane (15 ml) at room temperature was addedaqueous 6N HCl solution (0.05 ml). After being stirred for 30 minutes,the mixture was dried under reduced pressure to give(Z)-2-(8,9-dimethoxy-2,3-di-hydroimidazo[1,2-c]quinazolin-5-yl)-1-(3-pyridinyl)ethenolhydrochloride (18.5 mg, quantitative) as a yellow solid.

Melting point: >300° C.

Mass spectrometry: 351

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

¹H-NMR (500 MHz, DMSO-d6): δ 3.88 (3H, s), 4.00 (3H, s), 4.22 (2H, t, J=9.1 Hz), 4.55 (2H, t, J=9.1 Hz), 6.21 (1H, s), 7.60 (1H, s), 7.66 (1H,dd, J=4.7, 8.2 Hz), 7.90 (1H, s), 8.47 (1H, d, J=8.2 Hz), 8.79 (1H, d,J=4.7 Hz), 9.28 (1H, s), 14.9 (1H, bs).

Example 1-32-[7-Methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol(1) 4-Formyl-2-methoxy-3-nitrophenyl acetate

By the procedure described in U.S. Pat. No. 4,287,341 or J. Chem. Soc.376 (1948), vanillin acetate 5.00 g afforded the title compound 4.54 gas yellow solid. Yield 73.6%.

H-NMR (500 MHz, DMSO-d₆) δ: 2.40(s 3H), 3.87(s 3H), 7.75(d 1H J=8.4 Hz),7.94(d 1H J=8.4 Hz), 9.90(s 1H)

(2) 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde

A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 4.54 g (19.0 mmol)and potassium carbonate 5.24 g (37.9 mmol) in methanol 40 mL was stirredat room temperature for 2 hours. The reaction mixture was poured intowater, acidified by 1N HCl solution and extracted into AcOEt. Theorganic layer was washed with brine, dried over MgSO₄, filtrated and thesolvent was evaporated. The residue was washed with n-hexane to give thetitle compound 3.60 g as white solid. Yield 96.3%.

(3) 4-Hydroxy-3-methoxy-2-nitrobenzonitrile

To a mixture of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde 14.5 g (73.5mmol) in 28% ammonia solution 150 mL and tetrahydrofuran 15 mL was addediodine 22.4 g (88.2 mmol) and stirred at room temperature for overnight.The reaction mixture was concentrated in vacuo. The residue wasacidified with 2H HCl solution and extracted into diethyl ether. Theorganic layer was washed with brine, dried over MgSO₄, filtrated and thesolvent was evaporated. The residue was washed with diisopropyl ether togive the title compound 12.1 g as brown solid. Yield 84.5%

(4) 3-Methoxy-4-(methoxymethoxy)-2-nitrobenzonitrile

A mixture of 4hydroxy-3-methoxy-2-nitrobenzonitrile 1.00 g, chloromethylmethyl ether 0.47 mL (6.18 mmol) and potassium carbonate 3.56 g (25.8mmol) in N,N-dimethylformamide 10 mL was stirred at 50° C. for 2 hours.The reaction mixture was poured into water and extracted into diethylether. The organic layer was washed with brine, dried over MgSO₄,filtrated and the solvent was evaporated. Silica gel chromatography(n-hexane/AcOEt=4/1) afforded the title compound 1.03 g as colorlesssolid. Yield 83.5%.

(5) 2-Amino-3-methoxy-4-(methoxymethoxy)benzonitrile

To 5% palladium on activated carbon 6.00 g under argon atmosphere wasadded a solution of 3-methoxy-4-(methoxymethoxy)-2-nitrobenzonitrile6.00 g (25.2 mmol) in ethanol 50 mL and stirred under hydrogenatmosphere at room temperature for 8 hours. The reaction mixture wasfiltrated and the filtrate was concentrated in vacuo. Silica gelchromatography (n-hexane/AcOEt=4/1) afforded the title compound 2.83 gas white solid. Yield 53.9%.

(6)[6-(4,5-Dihydro-1H-imidazol-2-yl)-2-methoxy-3-(methoxymethoxy)phenyl]amine

A solution of 2-amino-3-methoxy-4-(methoxymethoxy)benzonitrile 475 mg(2.28 mmol) and phosphorus pentasulfide 25.4 mg (0.11 mmol) inethylenediamine 2.75 g was stirred at 120° C. for overnight. Thereaction mixture was cooled to room temperature and poured into water.The precipitate was collected and washed with water to give the titlecompound 293 mg as white solid. Yield 51.1%.

(7) Ethyl 3-oxo-3-(pyridin-3-yl)propanoate

To a suspension of nicotinic acid 5.00 g (40.6 mmol) in tetrahydrofuran50 mL was added carbonyl diimidazole 9.76 g (60.9 mmol) at 5° C. andstirred at room temperature for 1 hour. In a separate flask, asuspension of MgCl₂ 4.64 g (48.7 mmol) and ethyl malonate potassium salt10.37 g (60.92 mmol) in tetrahydrofuran 50 mL was stirred at 50° C. for4 hours. To this suspension was added the aforementioned imidazolidesolution at room temperature and stirred for 12 hours. The reaction wasquenched by the addition of water and extracted into ethyl acetate. Theorganic layer was washed by brine, dried over MgSO₄, filtrated and thesolvent was evaporated. Silica gel chromatography (n-hexane/AcOEt=2/1)afforded the titla compound 3.89 g as pale yellow oil. Yield 49.5%.

(8)2-[7-Methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol

A solution of[6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(methoxymethoxy)phenyl]amine1.31 g (5.20 mmol) and ethyl 3-oxo-3-(pyridin-3-yl)propanoate 1.00 g(5.20 mmol) in toluene 30 mL was refluxed for overnight. The precipitatewas collected and washed with diethyl ether to give the title compound1.52 g as a yellow solid. Yield 76.9%.

Melting point: 215-216° C.

Mass spectrometry: 381

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: B

H-NMR (500 MHz, CDCl₃) δ: 3.54(s 3H), 3.95(t 2H J=9.5 Hz), 4.08(s 3H),4.22(t 2H J=9.5 Hz), 5.30(s 2H), 5.38(s 1H), 6.98(d 1H J=8.8 Hz),7.37(dd 1H J=8.0 Hz, 4.9 Hz), 7.64(d 1H J=8.8 Hz), 8.21(dt 1H J=8.0 Hz,1.7 Hz), 8.67(dd 1H J=4.9 Hz, 1.7 Hz), 9.09(d 1H J=1.7 Hz), 13.75(s 1H)

Example 1-45-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olhydrochloride

A suspension of2-[7-methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol(Example 1-3) 1.52 g (4.00 mmol) in 4N HCl in 1,4-dioxane 30 mL andwater 0.3 mL was stirred at room temperature for overnight. The reactionmixture was diluted with diethyl ether. The precipitate was collectedand washed with diethyl ether to give the title compound 1.23 g as ayellow solid. Yield 82.4%

Melting point: 245° C.

Mass spectrometry: 337

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ: 3.97(s 3H), 4.22(dd 2H J=12.3 Hz, 9.0 Hz),4.43(dd 2H J=12.3 Hz, J=9.0 Hz), 6.17(s 1H), 7.10(d 1H J=9.0 Hz),7.71(dd 1H J=7.7 Hz, 4.7 Hz), 7.98(d 1H J=9.0 Hz), 8.57(br d 1H J=7.7Hz), 8.82 (dd 1H J=4.7 Hz, 1.4 Hz), 9.34(d 1H J=1.4 Hz), 11.79(s 1H),14.60(s 1H)

Example 1-5 Methyl4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoate

A mixture of5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-olhydrochloride (Example 1-4) 50.4 mg (0.14 mmol), methyl chloro-butyrate22.2 mg (0.16 mmmol) and potassium carbonate 186.9 mg (1.35 mmmol) inN,N-dimethylformamide 1 mL was stirred at 120° C. for 4 hours. Thereaction mixture was poured into water and extracted intodichloromethane. The organic layer was washed with brine, dried overMgSO₄, filtrated and the solvent was evaporated. The residue was washedby diethyl ether to give the title compound 35.0 mg as yellow solid.Yield 59.3%.

Melting point: 199-200° C.

Mass spectrometry: 437

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, CDCl₃) δ: 2.20(quint 2H J=7.1 Hz), 2.58(t 2H J=7.09 Hz),3.71(s 3H), 3.94(t 2H J=9.5 Hz), 4.06(s 3H), 4.15(t 2H J=7.1 Hz), 4.21(t2H J=9.5 Hz), 5.38(s 1H), 6.76(d 1H J=8.8 Hz), 7.37(dd 1H J=8.2 Hz, 5.2Hz), 7.65(d 1H J=8.8 Hz), 8.21(dt J=8.2 Hz, 2.1 Hz), 8.67(d 1H J=5.2Hz), 9.09(s 1H), 13.70(s 1H)

Example 1-6 Example 3-44-{[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoicacid

A solution of methyl4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoate(example 1-5) 20.0 mg (0.05 mmol) in 1N LiOH solution 0.1 mL and ethanol1.0 mL was stirred at room temperature for overnight. The reactionmixture was neutralized with 1N HCl solution and concentrated in vacuo.The residue was triturated in water. The precipitate was collected togive the title compound 10.0 mg as white solid. Yield 51.7%.

Melting point: 257-258° C.

Mass spectrometry: 423

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ: 2.02(quint 2H J=6.2 Hz), 2.45(t 2H J=6.2Hz), 3.94(s 3H), 3.98(br t 2H J=8.5 Hz), 4.06(br t 2H J=8.5 Hz), 4.14(t2H J=6.2 Hz), 5.67(s 1H), 6.97(d 1H J=8.7 Hz), 7.49(dd 1H J=8.2 Hz, 4.4Hz), 7.57(d 1H J=8.7 Hz), 8.29(d 1H J=8.2 Hz), 8.67(d 1H J=4.4 Hz),9.14(s 1H), 12.15(s 1H), 13.76(s 1H)

Example 1-74-{[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoicacid hydrochloride

A mixture of4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoicacid (Example 1-6) 4.0 mg (9.5 micromol) in 4N HCl in 1,4-dioxane 2.0 mLwas stirred at room temperature for 2 hours. The reaction mixture wasdiluted with diethyl ether. The precipitate was collected to give thetitle compound 4.00 mg as a yellow solid. Yield 92.0%.

Melting point: 249-251° C.

Mass spectrometry: 423

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ: 2.06(quint 2H J=7.3 Hz), 2.46(t 2H J=7.3Hz), 4.01(s 3H), 4.24(t 2H J=9.0 Hz), 4.29(t 2H J=7.3 Hz), 4.45(t 2HJ=9.0 Hz), 6.18(s 1H), 7.36(d 1H J=9.1 Hz), 7.70(dd 1H J=7.9 Hz, 5.0Hz), 8.14(d 1H J=9.1 Hz), 8.56(br d 1H J=7.9 Hz), 8.82(br d 1H J=5.0Hz), 9.34(s 1H), 12.34(s 1H), 14.57(s 1H)

Example 1-82-[7-Methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol

To a solution of4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl]oxy}butanoicacid (Example 1-6) 20.0 mg (0.044 mmol), morpholine 19.0 mg (0.22 mmol)and N,N-diisopropylethylamine 0.038 mL (0.22 mmol) inN,N-dimethylformamide 2.0 mL was addedPyBOP((1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphoniumhexafluorophosphate) 34.0 mg (0.065 mmol) and stirred at 80° C. forovernight. After cooling to room temperature, the reaction mixture waspoured into water. The precipitate was collected and washed with waterto give the title compound 13.0 mg as a white solid. Yield 60.7%.

Melting point: 234-235° C.

Mass spectrometry: 492

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ:2.03(quint 2H J=6.6 Hz), 3.46(m 4H), 3.56(m4H), 3.96(s 3H), 3.99(br d 2H J=8.2 Hz), 4.05(br d 2H J=8.2 Hz), 4.15(t2H J=6.6 Hz), 5.66(s 1H), 6.98(d J=8.8 Hz), 7.50(dd 1H J=7.7 Hz, 4.7Hz), 7.57(d 1H J=8.8 Hz), 8.29(br d 1H J=7.7 Hz), 8.67(br d 1H J=4.7Hz), 9.14(s 1H), 13.76(s 1H)

In a similar method according to the Example 1-1 to 1-8 above, thecompounds in Example 1-9 to 1-210 were synthesized. TABLE 1 Mol MS Ex.No. Structure Weight (M + 1) mp in vitro 1-9

372.81 337 245(dec.) A 1-10

350.38 351 269-270 A 1-11

386.84 351 249-250 A 1-12

407.43 408 270(dec.) A 1-13

364.41 365 267-268 A 1-14

378.43 379 252-253 A 1-15

390.45 391 254(dec.) B 1-16

380.41 381 264-265 A 1-17

416.87 381 215(dec.) A 1-18

450.50 451 184-186 B 1-19

407.48 408 183-184 B 1-20

447.54 448 162-163 B 1-21

433.51 434 204-205 A 1-22

430.85 395 240(dec.) A 1-23

393.41 394 297-298 A 1-24

429.87 394 235(dec.) A 1-25

443.89 408 240(dec.) A 1-26

471.95 436 245(dec.) A 1-27

421.46 422 241-242 A 1-28

457.92 422 205(dec.) A 1-29

463.50 464 235-235 A 1-30

499.96 464 240-241 A 1-31

537.98 502 230-231 B 1-32

391.43 392 >285   A 1-33

427.89 392 273 A 1-34

373.42 374 >285   A 1-35

409.88 374 270 A 1-36

449.51 450 197 A 1-37

485.97 450 215 A 1-38

543.03 507 260 A 1-39

433.51 434 217 B 1-40

469.98 434 256(dec.) B 1-41

527.03 491 271 A 1-42

350.38 351 218 A 1-43

386.84 351 290(dec.) A 1-44

476.76 442, 440 >290   B 1-45

419.71 385, 383 >290   B 1-46

476.76 442, 440 >285   A 1-47

442.29 424, 422 >285   B 1-48

458.75 424, 422 >285   B 1-49

364.41 365 200-204 A 1-50

400.87 365 260(dec.) B 1-51

443.89 408 275-280 B 1-52

379.42 380 321-325 B 1-53

393.45 394 195‥198 B 1-54

409.45 410 207 B 1-55

384.83 385 283 B 1-56

389.42 390 212-215 A 1-57

425.88 390 240(dec.) A 1-58

355.42 356 250 B 1-59

391.88 356 266-268 B 1-60

384.46 385 292 A 1-61

420.92 385 268-271 A 1-62

364.41 365 278 A 1-63

400.87 365 285 A 1-64

421.46 422 >285   A 1-65

457.92 422 >285 A 1-66

403.44 404 280 B 1-67

439.91 404 >285   B 1-68

320.35 321 275 A 1-69

356.81 321 285 A 1-70

308.32 309 218 A 1-71

344.78 309 303 B 1-72

324.77 325 210(dec.) B 1-73

369.22 371, 369 120(dec.) B 1-74

405.68 371, 369 246 B 1-75

304.35 305 248 B 1-76

340.82 305 >290   B 1-77

361.41 362 >285   A 1-78

397.87 362 >285   A 1-79

379.85 344 >285   A 1-80

358.33 359 275 B 1-81

394.79 359 >290   B 1-82

389.46 390 198-202 (dec.) B 1-83

342.79 307 >250 B 1-84

419.49 420 195-196 B 1-85

455.95 420 261-262 B 1-86

377.45 378 186-187 B 1-87

391.48 392 235(dec.) B 1-88

360.42 361 203(dec.) B 1-89

396.88 361 >300   B 1-90

420.47 421 222-223 A 1-91

350.38 351 211-212 B 1-92

364.41 365 203-205 A 1-93

348.36 349 225-226 B 1-94

375.43 376 282 B 1-95

411.89 376 >300   B 1-96

432.49 433 269(dec.) A 1-97

468.95 433 246 A 1-98

391.43 392 337(dec.) A 1-99

427.89 392 312(dec.) A 1-100

414.47 415 232 A 1-101

450.93 415 286(dec.) A 1-102

482.97 447 238(dec.) B 1-103

501.04 466 257 B 1-104

424.94 389 288 B 1-105

445.53 446 292(dec.) B 1-106

481.99 446 280(dec.) B 1-107

427.51 428 207 A 1-108

463.97 428 >300   B 1-109

416.49 416 A 1-110

438.92 403 231(dec.) B 1-111

389.46 390 204 B 1-112

425.92 390 242 B 1-113

446.51 447 245 B 1-114

482.97 447 260 B 1-115

428.50 429 219 B 1-116

324.77 325 226 B 1-117

361.23 326 280(dec.) B 1-118

405.68 371, 369 233 B 1-119

304.35 305 224 B 1-120

340.82 305 >330   B 1-121

358.33 359 264 C 1-122

394.79 359 321 B 1-123

402.89 >300   B 1-124

306.33 307 302-303 B 1-125

342.79 307 >300   A 1-126

320.35 321 199 B 1-127

356.81 321 >300   B 1-128

399.84 364 >300   A 1-129

405.68 371, 369 >300 B 1-130

361.23 326 >330   B 1-131

304.35 305 212 B 1-132

340.82 305 >290   B 1-133

346.39 347 >300   B 1-134

290.33 291 202 B 1-135

326.79 291 260(dec.) B 1-136

304.35 305 217-219 B 1-137

340.82 305 >300   B 1-138

383.84 348 327 A 1-139

319.37 320 232-237 A 1-140

347.42 348 197 B 1-141

291.31 292 233-235 B 1-142

327.78 292 217-222 B 1-143

279.30 280 192 B 1-144

315.76 280 >300   B 1-145

279.30 280 155-156 B 1-146

295.37 296 193 A 1-147

381.83 296 >300   A 1-148

295.37 296 182-183 B 1-149

331.83 296 >300   A 1-150

278.32 279 247 B 1-151

278.32 279 247-249 A 1-152

280.29 281 148 B 1-153

316.75 281 245(dec.) B 1-154

296.35 297 208-210 A 1-155

332.81 297 >300   B 1-156

324.41 325 222 A 1-157

365.83 330 >300   B 1-158

330.60 330 190(dec.) B 1-159

330.35 331 >300   A 1-160

366.81 331 247(dec.) B 1-161

362.39 363 >300   B 1-162

399.84 400 >300   B 1-163

419.49 420 200 B 1-164

291.31 292 230 B 1-165

291.31 292 250 B 1-166

289.34 290 130-139 C 1-167

334.34 335 276 D 1-168

334.34 335 240-248 D 1-169

319.37 320 212-214 D 1-170

305.34 306 252-256 D 1-171

323.78 324 224-227 D 1-172

315.35 315 260-264 D 1-173

290.33 291 195 C 1-174

326.79 291 235-240 C 1-175

290.33 291 204-205 B 1-176

326.79 291 235(dec.) B 1-177

320.38 321 256 C 1-178

340.36 341 255-258 D 1-179

425.51 426 >300   D 1-180

345.43 346 220-225 D 1-181

381.89 346 >300   D 1-182

255.32 256 113 D 1-183

269.35 270 134-138 C 1-184

281.24 282 240 C 1-185

349.39 350 249-252 C 1-186

383.84 384 257-259 D 1-187

374.40 375 307-308 D 1-188

358.33 359 264 C 1-189

324.77 325 260 C 1-190

323.78 324 186-188 C 1-191

334.34 335 259-262 D 1-192

335.32 336 306 C 1-193

317.39 318 156-160 D 1-194

434.50 435 233-234 A 1-195

375.39 376 284-285 A 1-196

418.42 419 229-231 A 1-197

454.88 419 217-218 A 1-198

528.01 492 215-216 A 1-199

436.47 437 178-179 A 1-200

430.85 395 286(dec.) B 1-201

398.85 363 273(dec.) A 1-202

413.87 378 285(dec.) B 1-203

405.46 406 228 B 1-204

447.50 448 262 C 1-205

445.53 446 246 B 1-206

427.89 392 267 A 1-207

425.92 390 259(dec.) B 1-208

446.51 447 253(dec.) B 1-209

482.97 447 >260   B 1-210

464.96 429 >300   A

Example 2-1 N-(2,3-Dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (1)2-(4,5-Dihydro-1H-imidazol-2-yl)aniline

2-Aminobenzonitrile (9.00 g, 76.2 mmol) was added at 0° C. toethylenediamine (25.5 ml, 381 mmol) in small portions with stirring.After phosphorus pentasulfide (200 mg, 0.900 mmol) was added, themixture was stirred at 100° C. overnight. After cooling to 0° C., thereaction was diluted with water. The resulting white precipitate wascollected by filtration, washed with water and diethyl ether, and driedunder reduced pressure to give 2-(4,5-dihydro-1H-imidazol-2-yl)aniline(10.0 g, 81% yield).

(2) 2,3-Dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide

To a suspension of 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (5.00 g, 31.0mmol) in 85% methanol (60 ml) at 0° C. was added cyanogen bromide (3.61g, 34.1 mmol) by portions. This mixture was stirred at room temperatureovernight. After the mixture was concentrated under reduced pressure,the resulting precipitate was collected by filtration. This pale greensolid was washed with water, methanol and diethyl ether successively,and dried under reduced pressure to give2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (4.94 g, 60%yield).

(3) N-(2,3-Dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

To a suspension of 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylaminehydrobromide (500 mg, 1.87 mmol) and nicotinic acid (346 mg, 2.81 mmol)in N,N-dimethyl-formamide (25 ml) at room temperature was addedbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(1.46 g, 2.81 mmol) followed by N,N-diisopropylethylamine (1.30 ml, 7.49mmol). The mixture was heated at 80° C. for 4 hours. After cooling toroom temperature, the mixture was quenched with aqueous saturated NaHCO₃solution. The resulting precipitate was collected by filtration, washedwith water and diethyl ether, and dried under reduced pressure to giveN-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (450 mg, 83%yield).

Melting point: 238-239° C. (decomposition)

Mass spectrometry: 292

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

¹H-NMR (300 MHz, DMSO-d6): d 4.00-4.11 (2H, m), 4.11-4.21 (2H, m), 7.29(1H, ddd, J=3.0, 5.3, 7.9 Hz), 7.52 (1H, dd, J=4.9, 7.9 Hz), 7.57-7.66(2H, m), 7.89 (1H, d, J=7.9 Hz), 8.42-8.48 (1H, m), 8.73 (1H, dd, J=1.9,4.9 Hz) 9.32 (1H, d, J=1.1 Hz), 12.36 (1H, s).

Example 2-2 N-(2,3-Dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamidehydrochloride

To a suspension ofN-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (150 mg, 0.515mmol) in tetrahydrofuran (4 ml) at 0° C. was added a 4N solution ofhydrochloric acid in 1,4-dioxane (2 ml, 8 mmol). The mixture was stirredat room temperature for 1 h, and concentrated under reduced pressure.The resulting residue was triturated with diethyl ether. The resultingprecipitate was collected by filtration, washed with ethyl ether, anddried under reduced pressure to giveN-(2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)nicotinamide hydrochloride(192 mg, quantitative).

Melting point: 289° C. (decomposition)

Mass spectrometry: 292

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

¹H-NMR (300 MHz, DMSO-d6): δ 4.18-4.30 (2H, m), 4.54-4.65 (2H, m),7.56-7.65 (1H, m), 7.88 (1H, dd, J=4.9, 7.9 Hz), 7.97-8.10 (2H, m), 8.64(1H, d, J=7.9 Hz), 8.80 (1H, d, J=7.9 Hz), 8.95 (1H, dd, J=1.5, 5.3 Hz),9.43 (1H, d, J=1.1 Hz), 12.7-13.3 (1H, br).

Example 2-36-(Acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide(1) 4-(Morpholin-4-yl)-2-nitrobenzonitrile

A mixture of 2,4-dinitrobenzonitrile 4.20 g (21.75 mmol) and morpholine5.7 mL (66.0 mmol) in N,N-dimethyformamide 20 mL was stirred at roomtemperature for 20 hours. The reaction mixture was poured into water.The precipitate was collected and washed with water to give the titlecompound 4.20 g as orange solid. Yield 74.5%.

(2) 2-Amino-4-(morpholin-4-yl)benzonitrile

To a cooled mixture of tin(II) chloride dihydrate 12.8 g (56.7 mmol) inconc. HCl 40 mL with ice bath was added4-(morpholin-4-yl)-2-nitrobenzonitrile 4.20 g (16.09 mmol) and stirredat room temperature for 2 hours. The reaction mixture was poured intodiluted NaOH solution and extracted into ethyl acetate. The organiclayer was washed with water and brine, dried over MgSO₄ and the solventwas evaporated. The crude product was washed with diethyl ether to givethe title compound 3.13 g as off-white solid. Yield 95.0%.

(3) [2-(4,5-dihydro-1H-imidazol-2-yl)-5-(morpholin-4-yl)phenyl]amine

To a solution of 2-amino-4-(morpholin-4-yl)benzonitrile 3.65 g (18.0mmol) in ethylenediamine 20 mL was added phosphorus pentasulfide 4.00 mg(0.018 mmol) and stirred at 140° C. for 16 hours. After cooling to roomtemperature, the solvent was evaporated. The residue was washed withwater and diethyl ether to give the title compound 3.70 g as off-whitesolid. Yield 83.5%.

(4) 8-(Morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-aminehydrobromide

To a suspension of[2-(4,5-dihydro-1H-imidazol-2-yl)-5-(morpholin-4-yl)phenyl]amine 3.60 g(14.6 mmol) in 2-propanol 20 mL was added cyanogen bromide 2.32 g(21.9mmol) portionwise at 0° C. and stirred at 100° C. for 2 hours.After cooling to room temperature, the precipitate was collected andwashed with diethyl ether to give the title compound 1.20 g as yellowsolid. Yield 77.5%.

(5) 6-(Acetamido)nicotinic acid

A mixture of 6-aminonicotinic acid 5.00 g (36.5 mmol) and aceticanhydride 3.80 mL (40.2 mmol) in pyridine 30 mL was stirred at 140° C.for 24 hours. To the reaction mixture was added ethyl acetate andacidified with diluted HCl solution to pH 2. The organic layer waswashed with water and brine, dried over MgSO₄, filtrated and the solventwas evaporated. The residue was washed with diisopropyl ether to givethe title compound 1.70 g as off-white solid. Yield 26%.

(6)6-(Acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide

To a mixture of8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-aminehydrobromide 105.7 mg (0.30 mmol), 6-(acetamido)nicotinic acid 81.1 mg(0.45 mmol) and N,N-diisopropylethylamine 0.26 mL (1.50 mmol) inN,N-dimethylformamide 2 mL was addedPyBOP((1H-1,2,3-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)-phosphoniumhexafluorophosphate) 234.2 mg (0.45 mmol) and stirred at 90° C. for 16hours. After cooling to room temperature, saturated NaHCO₃ solution wasadded. The precipitate was collected and washed with water, methanol,and diethyl ether to give the title compound 41.1 mg as yellow solid.Yield 31.6%.

Melting point: 228° C.

Mass spectrometry: 434

In vitro PI3Kβ inhibitory activity: C

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ: 3.22-3.30 (m 4H), 3.74 (s 3H), 3.86 (m 2H),3.97 (m 2H), 6.77 (br s 1H), 7.60 (m 1H), 8.07 (m 1H), 8.32 (m 1H), 8.95(br s 1H), 10.60 (s 1H)

Example 2-46-(Acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamidehydrochloride

To a mixture of6-(acetamido)-N-[8-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-c]-quinazolin-5-yl]nicotinamide(Example 2-3) 20.0 mg (0.046 mmol) in 1,4-dioxane 1.5 mL was added 4NHCl in 1,4-dioxane 0.5 mL and stirred at room temperature for 40minutes. The precipitate was collected and washed with diethyl ether togive the title compound 17.0 mg as yellow solid. Yield 78%.

Melting point: 237° C.

Mass spectrometry: 434

In vitro PI3K-β inhibitory activity: B

In vitro PI3K-γ inhibitory activity: A

H-NMR (500 MHz, DMSO-d₆) δ: 3.41-3.76 (m 7H), 3.86 (m 2H), 4.10 (m 2H),7.20 (m 1H), 7.39 (m 1H), 8.19 (m 1H), 8.45 (m 1H), 9.09 (br s 1H),10.86 (s 1H)

Example 2-5N-(8-Hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide

A suspension ofN-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide(example 2-22) 3.50 g (10.9 mmol) and sodium sulfide 4.25 g (54.5 mmol)in 1-methyl-2-pyrrolidinone 10 mL was heated to 160° C. for 4 hours(LC-MS indicated complete consumption of the starting material). Themixture was cooled to room temperature and volatile sideproducts wereevaporated. The mixture was partitioned between chloroform and 0.5N NaOHsolution. The aqueous layer was neutralized and the formed precipitatewas collected to give the title compound 2.34 g as off-white solid.Yield 69.9%.

Melting point: 289° C.

Mass spectrometry: 308

In vitro PI3K-β inhibitory activity: C

In vitro PI3K-γ inhibitory activity: B

H-NMR (500 MHz, DMSO-d₆) δ: 4.01(m 2H), 4.15(m 2H), 6.75(dd 1H J=8 Hz, 2Hz), 6.91(s 1H), 7.52(dd 1H J=8 Hz, 5 Hz), 7.75(d 1H J=8 Hz), 8.44(d 1HJ=8 Hz), 8.73(dd 1H J=5 Hz, 2 Hz), 9.31(s 1H), 10.61(br s 1H), 12.24(brs 1H)

Example 2-6N-{8-[2-(1-pyrrolyl)ethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide

The suspension ofN-(8-Hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide(example 2-1) 70.0 mg (0.23 mmol), N-(2-bromoethyl)pyrrole 47.6 mg (0.27mmol) and potassium carbonate 126 mg (0.91 mmol) inN,N-dimethylformamide 5 mL was heated in a sealed tube to 120° C. for 3hours. The reaction mixture was concentrated and partitioned betweendichloromethane and water. The organic layer was washed with 0.1N NaOHsolution and brine, dried over Na₂SO₄ and the solvent was evaporated togive the title compound 49.0 mg as off-white solid. Yield 54%.

Melting point: 209° C.

Mass spectrometry: 401

In vitro PI3Kβ inhibitory activity: B

In vitro PI3K-γ inhibitory activity: B

H-NMR (500 MHz, DMSO-d₆) δ: 4.00(m 2H), 4.12(m 2H), 4.30(s 4H), 6.00(m2H), 6.84(m 2H), 6.85(dd 1H J=6 Hz, 2 Hz), 7.27(d 1H J=2 Hz), 7.52(dd 1HJ=6 Hz), 7.76(d 1H J=8Hz), 8.44(dd 1H J=8 Hz, 2 Hz), 8.72(dd 1H J=5 Hz,2 Hz), 9.31(s 1H), 12.32(s 1H)

In a similar method according to the Example 2-1 to 2-6 above, thecompounds in Example 2-7 to 2-368 were synthesized. TABLE 2 in vitro Ex.PI3K- No. Structure MW MASS mp/° C. gamma 2-7

376.42 377 243 B 2-8

412.88 377 283 A 2-9

468.95 433 249 B 2-10

415.46 416 250(dec.) B 2-11

451.92 416 294(dec.) A 2-12

390.45 391 199(dec.) B 2-13

390.45 391 209 A 2-14

426.91 391 267(dec.) A 2-15

432.49 433 227 B 2-16

410.50 411 233(dec.) B 2-17

446.96 411 255(dec.) A 2-18

407.48 408 232 B 2-19

410.91 376 >300 B 2-20

321.34 322 281(dec.) B 2-21

357.80 322 292(dec.) B 2-22

414.85 379 198-205(dec.) B 2-23

336.36 337 279-282 A 2-24

372.82 337 273(dec.) A 2-25

360.38 361 186 A 2-26

396.84 361 233 A 2-27

305.34 306 207 A 2-28

341.80 306 315 A 2-29

344.38 345 190 A 2-30

380.84 345 295 B 2-31

310.38 311 182 B 2-32

346.84 311 276 B 2-33

359.31 360 229 B 2-34

395.77 360 275 A 2-35

411.77 375 237(dec.) A 2-36

398.35 399 >300 B 2-37

434.81 399 288 A 2-38

362.22 327 308 B 2-39

364.80 366 288 A 2-40

401.26 366 270 A 2-41

367.26 332 328 B 2-42

406.67 372, 370 243 A 2-43

420.70 386, 384 252(dec.) B 2-44

409.25 411, 409 262 B 2-45

445.71 411, 409 278 A 2-46

351.37 352 259-260 A 2-47

387.83 352 257-257 A 2-48

408.42 409 306-307 A 2-49

390.40 391 289(dec.) A 2-50

426.87 391 278(dec.) A 2-51

391.39 392 233(dec.) A 2-52

427.85 392 210(dec.) A 2-53

387.83 352 246 B 2-54

367.37 367 287(dec.) A 2-55

403.83 367 260(dec.) A 2-56

402.84 367 256 B 2-57

408.42 409 224 B 2-58

444.88 409 279 B 2-59

401.86 366 257(dec.) B 2-60

390.40 391 246 A 2-61

426.87 391 276 A 2-62

356.41 357 248 B 2-63

376.81 340 270(dec.) B 2-64

368.40 368 236-237 B 2-65

400.24 402, 400 264 A 2-66

436.70 402, 400 298 A 2-67

436.70 402, 400 289(dec.) B 2-68

351.37 352 228(dec.) A 2-69

387.83 352 275(dec.) B 2-70

408.42 408 286(dec.) B 2-71

444.88 408 270(dec.) B 2-72

390.40 391 210(dec.) A 2-73

426.87 391 289(dec.) A 2-74

420.70 386, 384 220 A 2-75

423.28 425, 423 >290 B 2-76

401.86 366 235(dec.) B 2-77

379.42 379 210(dec.) A 2-78

415.88 379 230(dec.) A 2-79

422.45 422 >310 B 2-80

458.91 422 305(dec.) A 2-81

404.43 405 202 B 2-82

440.89 405 280(dec.) B 2-83

384.80 349 >300 B 2-84

325.76 326 210 B 2-85

362.22 327 309 B 2-86

401.26 366 305(dec.) B 2-87

370.21 372 228 B 2-88

406.67 372, 370 316 B 2-89

445.71 411, 409 288 B 2-90

305.34 306 210 A 2-91

341.80 306 >290 B 2-92

380.84 345 >290 A 2-93

357.80 322 >300 B 2-94

396.84 361 288 A 2-95

317.35 318 196-198 B 2-96

353.81 318 275-277 B 2-97

393.84 358 298-299 B 2-98

362.22 327 249 B 2-99

309.31 310 243 B 2-100

345.77 310 288 A 2-101

348.34 349 >300 A 2-102

384.80 349 >300 A 2-103

362.22 326 >280 B 2-104

382.81 383 >280 B 2-105

419.27 383 >280 A 2-106

401.26 365 >280 B 2-107

305.34 306 244 B 2-108

341.80 306 >290 B 2-109

344.38 345 >290 A 2-110

380.84 345 >290 A 2-111

395.77 360 263 A 2-112

398.35 399 286 A 2-113

434.81 399 270 A 2-114

321.34 322 110 A 2-115

357.80 322 237(dec.) A 2-116

335.37 335 204-205 B 2-117

371.83 335 251(dec.) A 2-118

355.79 355 185(dec.) A 2-119

392.25 355 266(dec.) A 2-120

371.83 335 220(dec.) A 2-121

389.34 389 144-145 B 2-122

373.80 338 285(dec.) A 2-123

372.82 337 296 A 2-124

360.38 361 287 A 2-125

396.84 361 238 A 2-126

386.42 386 183-184 A 2-127

422.88 386 225(dec.) A 2-128

440.39 440 214(dec.) A 2-129

476.85 440 225(dec.) A 2-130

405.34 292 237-239 A 2-131

305.34 306 193-194 B 2-132

341.80 306 277(dec.) B 2-133

306.33 306 215(dec.) B 2-134

325.76 326 198-199 A 2-135

362.22 326 340(dec.) B 2-136

305.34 305 194-195 B 2-137

341.80 305 291(dec.) B 2-138

307.31 307 273(dec.) A 2-139

343.78 307 296-297 A 2-140

321.34 321 219(dec.) B 2-141

357.80 321 272(dec.) B 2-142

335.32 336 358-359 B 2-143

384.42 385 265-269 A 2-144

306.33 307 263-266 A 2-145

420.35 307 220(dec.) B 2-146

361.41 362 219(dec.) B 2-147

305.34 306 195-196 A 2-148

341.80 306 310(dec.) A 2-149

306.33 307 >300 A 2-150

342.79 307 290(dec.) A 2-151

348.37 349 320(dec.) A 2-152

384.83 349 312(dec.) A 2-153

320.36 320 196-197 B 2-154

356.82 320 300(dec.) B 2-155

362.22 326 324(dec.) B 2-156

376.25 340 287(dec.) B 2-157

320.36 321 146-148 B 2-158

356.82 321 289(dec.) B 2-159

320.36 320 246-247 B 2-160

356.82 320 311(dec.) B 2-161

370.84 334 298(dec.) B 2-162

419.37 306 191(dec.) B 2-163

419.37 306 232(dec.) B 2-164

461.40 348 247(dec.) A 2-165

328.76 292 291(dec.) B 2-166

444.38 331 221(dec.) A 2-167

380.84 345 333(dec.) B 2-168

329.36 330 160(dec.) B 2-169

365.83 330 295(dec.) B 2-170

344.38 345 277-279 B 2-171

380.84 345 328(dec.) B 2-172

331.34 332 >300 A 2-173

367.80 332 287(dec.) A 2-174

356.39 356 296(dec.) B 2-175

392.82 356 270(dec.) B 2-176

446.82 410 248-249 B 2-177

342.36 342 275(dec.) B 2-178

296.35 297 187-188 B 2-179

332.81 297 310(dec.) A 2-180

330.80 330 198-199 B 2-181

367.26 330 298(dec.) B 2-182

346.84 310 >250 B 2-183

296.35 297 167(dec.) B 2-184

332.81 297 297(dec.) B 2-185

280.29 280 217-218 B 2-186

331.76 295 285(dec.) B 2-187

345.79 309 280-281 B 2-188

333.80 298 306(dec.) B 2-189

325.39 326 243(dec.) B 2-190

361.86 326 289-290 A 2-191

322.37 322 207-208 B 2-192

358.83 322 271-272 B 2-193

280.29 281 265(dec.) B 2-194

316.75 281 309-310 B 2-195

343.78 308 270-274(dec.) B 2-196

436.90 401 239 B 2-197

351.37 352 210-215(dec.) B 2-198

387.83 352 249(dec.) B 2-199

365.39 366 127 A 2-200

401.86 366 243(dec.) B 2-201

395.42 396 181 B 2-202

431.88 396 229(dec.) B 2-203

401.81 366 231(dec.) B 2-204

406.40 407 265-269(dec.) B 2-205

456.94 421 243-247(dec.) B 2-206

364.37 365 296 B 2-207

434.46 435 232-236(dec.) B 2-208

470.92 435 227 B 2-209

530.98 495 247 A 2-210

307.31 308 >300 B 2-211

343.78 308 >300 A 2-212

346.35 347 296(dec.) B 2-213

346.35 347 209 B 2-214

290.33 291 201-203(dec.) C 2-215

404.35 291 238-242 B 2-216

304.35 305 201-203 D 2-217

418.38 305 239-241 B 2-218

304.35 305 185-186 D 2-219

318.38 319 246-248 D 2-220

348.41 349 216-218 D 2-221

384.87 349 288(dec.) D 2-222

363.38 364 277(dec.) D 2-223

399.84 364 313(dec.) D 2-224

308.32 309 202-204 C 2-225

308.32 309 210-212 D 2-226

438.80 325 221-224 D 2-227

324.77 325 196-197 D 2-228

438.80 325 233-235 C 2-229

324.77 325 226-228 D 2-230

438.80 325 243-245 D 2-231

359.22 358 268-269 D 2-232

320.35 321 185-187 D 2-233

320.35 321 202-204 D 2-234

434.38 321 209-211 C 2-235

320.35 321 300(dec.) D 2-236

362.44 363 >410 D 2-237

386.84 351 259(dec.) D 2-238

386.84 351 274(dec.) B 2-239

350.38 351 330(dec.) D 2-240

416.87 381 291(dec.) D 2-241

364.41 365 248(dec.) D 2-242

400.87 365 321(dec.) D 2-243

336.42 337 169-170 D 2-244

372.88 337 292(dec.) D 2-245

368.42 369 278(dec.) D 2-246

404.88 369 320(dec.) D 2-247

369.40 370 278(dec.) C 2-248

405.87 370 308(dec.) C 2-249

403.85 403 240(dec.) D 2-250

440.31 403 300(dec.) D 2-251

449.35 336 198-200 D 2-252

335.32 334 265-267 D 2-253

449.35 336 238-239 D 2-254

335.32 334 279-281 D 2-255

449.35 336 265(dec.) D 2-256

429.36 316 248-250 D 2-257

419.37 306 175(dec.) D 2-258

333.40 334 188-190 D 2-259

369.86 334 266(dec.) D 2-260

447.42 334 240(dec.) D 2-261

388.48 389 218-222 D 2-262

461.40 348 253(dec.) D 2-263

347.38 348 208-210 D 2-264

383.84 348 304(dec.) D 2-265

405.46 406 280(dec.) D 2-266

355.40 356 218-220 D 2-267

391.86 356 309(dec.) D 2-268

356.39 357 267(dec.) D 2-269

392.85 357 324(dec.) D 2-270

356.39 357 209-211 D 2-271

392.85 357 319(dec.) D 2-272

348.36 349 224-226 D 2-273

348.36 349 253-255 D 2-274

434.46 435 289(dec.) D 2-275

470.92 435 282 D 2-276

291.31 292 204-205 C 2-277

405.34 292 206(dec.) C 2-278

291.31 292 224-225 C 2-279

405.34 292 2310(dec.) C 2-280

359.31 360 219-220 D 2-281

395.77 360 >250 C 2-282

334.38 335 249(dec.) D 2-283

370.84 335 311(dec.) C 2-284

343.78 308 346(dec.) D 2-285

321.34 322 198-199 C 2-286

351.37 352 244-245 D 2-287

387.83 352 210(dec.) C 2-288

337.41 338 233-234 D 2-289

373.87 338 298-299 C 2-290

339.79 340 213-214 B 2-291

325.76 326 246-247 B 2-292

292.30 293 267-268 C 2-293

406.33 293 234(dec.) C 2-294

306.33 307 257(dec.) C 2-295

420.35 307 231(dec.) C 2-296

293.33 294 128-129 C 2-297

329.79 294 264(dec.) C 2-298

280.29 281 350(dec.) C 2-299

316.75 281 311(dec.) C 2-300

394.31 281 230-232 B 2-301

330.80 331 198(dec.) D 2-302

310.38 311 192-193 C 2-303

341.35 342 286-287 D 2-304

377.81 342 300(dec.) D 2-305

341.35 342 269-270 D 2-306

377.81 342 296(dec.) D 2-307

298.33 299 219(dec.) C 2-308

380.84 345 344(dec.) B 2-309

440.43 441 250-253 D 2-310

445.36 332 252(dec.) B 2-311

373.42 374 202-203 D 2-312

347.40 348 303-305 D 2-313

383.86 348 314(dec.) C 2-314

343.39 344 259-260 D 2-315

343.39 344 288-289 D 2-316

341.38 342 263-264 D 2-317

377.84 342 319(dec.) B 2-318

377.84 342 316(dec.) D 2-319

374.43 375 260-261 D 2-320

410.89 375 310(dec.) D 2-321

374.43 375 281(dec.) D 2-322

410.89 375 335(dec.) D 2-323

334.38 335 167-168 D 2-324

310.38 311 122-123 D 2-325

320.35 321 149-150 D 2-326

228.26 229 189 D 2-327

242.28 243 amorphous D 2-328

256.31 257 121-122 D 2-329

270.34 271 154(dec.) D 2-330

256.31 257 104-105 D 2-331

270.34 271 135-136 D 2-332

331.59 331 194(dec.) C 2-333

332.23 333 210-211 D 2-334

254.29 255 164-165 D 2-335

296.38 297 170-172 D 2-336

397.48 398 amorphous D 2-337

431.50 432 119-120 D 2-338

397.48 398 147-148 D 2-339

297.36 298 179-180 D 2-340

397.48 398 amorphous D 2-341

431.50 432 111-112 D 2-342

350.38 351 amorphous C 2-343

288.31 289 240-241 D 2-344

302.34 303 224-225 D 2-345

334.38 335 269 C 2-346

339.42 340 272 D 2-347

376.42 377 244 D 2-348

381.46 382 124 D 2-349

364.35 365 226 B 2-350

400.81 365 292 C 2-351

375.25 376 232 D 2-352

411.71 376 275 C 2-353

325.76 326 254 B 2-354

330.80 331 228 C 2-355

330.80 331 174 C 2-356

367.26 331 276 B 2-357

325.76 326 243 C 2-358

330.80 331 233 D 2-359

367.26 331 227 C 2-360

309.31 310 242 C 2-361

314.34 214 315 C 2-362

450.34 336 224 C 2-363

341.80 306 204(dec.) D 2-364

383.88 348 230-240 D 2-365

370.80 335 274(dec.) D 2-366

341.80 306 270(dec.) D 2-367

428.88 398 273-274 A 2-368

403.83 368 240(dec.) A

Example 3-1 (Z)-2-Imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol (1)2-(1H-Imidazol-2-yl)aniline

A mixture of 2-(4,5-dihydro-IH-imidazol-2-yl)aniline hydrobromide (50.0mg, 0.207 mmol) and manganese dioxide (170 mg, 1.96 mmol) inN,N′-dimethylpropylenurea (2.0 mL) was heated at 150. (bath temp.).After 1 hour, the reaction mixture was cooled to room temperature,poured into a solution of hydroxylamine hydrochloride (0.5 g) in water(50 mL), and the resulting mixture was extracted with ethyl acetate. Theseparated organic layer was washed with brine, dried over magnesiumsulfate, filtered, concentrated under reduced pressure. The cruderesidue was triturated with isopropylether, and the precipitate wasremoved by filtration. The filtrate was concentrated under reducedpressure, and the residue was purified by preparative thin layerchromatography (silica-gel, ethyl acetate as the eluent) to give2-(1H-imidazol-2-yl)aniline (20 mg, 61% yield).

(2) Ethyl 3-oxo-3-(2-thienyl)propanoate

To a suspension of 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) intetrahydrofurane (100 ml) at 5. was added 1,1′-Carbonyldiimidazole (8.61g, 53.09 mmol) by portions. The mixture was allowed to warm to roomtemperature, and the stirring was continued for 1 hour. The reactionmixture was added into a suspension mixture of magnesium chloride (4.86g, 51.07 mmol) and pottasium 3-ethoxy-3-oxopropanoate (12.91 g, 75.85mmol) in tetrahydrofurane (50 ml). After being stirred at 50. for 2hours and at room temperature overnight, the reaction mixture was pouredinto water ,and then extracted with ethyl acetate. The extract waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica-gel (ethyl acetate/hexane, 15/85) to give ethyl3-oxo-3-(2-thienyl)propanoate (7.83 g, 78% yield) as a yellow oil.

(3) (Z)-2-Imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol

A mixture of 2-(1H-imidazol-2-yl)aniline (60.0 mg, 0.38 mmol),ethyl3-oxo-3-(2-thienyl)propanoate (74.7 mg, 0.38 mmol) andp-tolenesulfonicacid monohydrate (36.1 mg, 0.19 mmol) in toluene (30 ml)was heated at reflux for 2 hours. After cooling to room temperature, thereaction mixture was poured into aqueous saturate NaHCO₃ solution, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica-gel (ethyl acetate/hexane, 2/3-1/1) to give(Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol (37.0 mg, 33%yeild) as a yellow powder.

Melting point: 128° C.

Mass spectrometry: 294

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: D

¹H-NMR (300 MHz, CDCl₃): d 6.11 (1H, s), 7.16 (1H, dd, J=3.8, 4.9 Hz),7.34-7.41 (2H, m), 7.53-7.60 (3H, m), 7.64 (1H, d, J=1.7 Hz), 7.73 (1H,dd, J=1.1, 2.8 Hz), 8.34 (1H, dd, J=0.9, 7.8 Hz), 14.70 (1H, bs).

Example 3-2 (Z-2-Imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenolhydrochloride

To a solution of (Z-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol(0.06 g, 0.07 mmol) in chloroform (1.0 ml) was added a 4N solution ofHCl in 1,4-dioxane (0.5 ml). The mixture was diluted with ethyl ether,and the resulting precipitate was collected by filtration, washed withethyl ether, and dried under reduced pressure to give(Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol hydrochloride(0.07 g, quantative) as a yellow solid.

Melting point: 263° C. (decomposition)

Mass spectrometry: 294

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: D

¹H-NMR (300 MHz, DMSO-d6): δ 6.79 (1H, s), 7.28 (1H, dd, J=3.8, 4.9 Hz),7.45 (1H, t, J=7.0 Hz), 7.66-7.77 (2H, m), 7.82 (1H, d, 1.7), 7.91 (1H,dd, J=1.1, 5.0 Hz), 8.17 (1H, dd, J=1.1, 3.8 Hz), 8.30 (1H, dd, J=1.0,8.0 Hz), 8.62 (1H, d, J=1.7 Hz), 14.36 (1H, br).

Example 4-1 N-Imidazo[1,2-c]quinazolin-5-ylnicotinamide (1)Imidazo[1,2]quinazolin-5-amine

To a solution of 2-(1H-imidazol-2-yl)aniline (0.06 g. 0.38 mmol) inmethanol (3 ml) was added cyanogen bromide (0.05 g, 0.45 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting precipitatewas collected by filtration, washed with acetone, and dried underreduced pressure to give imidazo[1,2-c]quinazolin-5-amine hydrobromide(0.06 g, 61% yield) as a white solid.

(2) N-Imidazo[1,2-c]quinazolin-5-ylnicotinamide

To a mixture of imidazo[1,2-c]quinazolin-5-amine hydrobromide (93 mg,0.35 mmol) and nicotinic acid (124 mg, 1.01 mmol) and DMF (2.5 ml) atroom temperature was addedbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(525 mg, 1.01 mmol) followed by N,N-diisopropylethyl amine (0.264 ml,1.51 mmol), and the mixture was stirred at 80. for 6 hours. Aftercooling to room temperature, the reaction mixture was poured intoaqueous saturated NaHCO₃ solution. The resulting precipitate wascollected by filtration, washed with acetone, and dried under reducedpressure to give N-imidazo[1,2-c]quinazolin-5-ylnicotinamide (40 mg, 39%yield) as a white solid.

Melting point: 223-224° C. (decomposition)

Mass spectrometry: 290

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: C

¹H-NMR (300 MHz, DMSO-d6): d 7.53-7.62 (3 H, m), 7.70 (1H, t, J=7.34Hz), 8.00 (1H, d, J=8.10 Hz), 8.30 (1H, d, J=7.91 Hz), 8.44 (1H, s),8.63 (1H, d, J=7.72 Hz), 8.81 (1H, dd, J=1.5, 4.7 Hz), 9.49 (1H, s),13.49 (1H, br).

Example 4-2 N-Imidazo[1,2-c]quinazolin-5-ylnicotinamide hydrochloride

To a solution of N-imidazo[1,2-c]quinazolin-5-ylnicotinamide (40 mg,0.14 mmol) in methanol (20 ml) was added a 4N solution of HCl in1,4dioxane (0.5 ml). The mixture was concentrated under reducedpressure. The resulting solid was collected by filtration, washed withtetrahydrofurane and dried under reduced pressure to giveN-imidazo[1,2-c]quinazolin-5-ylnicotinamide hydrochloride (40 mg, 89%yield) as a white solid.

Melting point: 228° C. (decomposition)

Mass spectrometry: 290

In vitro PI3K-β inhibitory activity:

In vitro PI3K-γ inhibitory activity: C

¹H-NMR (300 MHz, DMSO-d6): δ 7.60 (2H, br), 7.65 (1H, t, J=7.5 Hz), 7.82(1H, dd, J=7.3, 8.1 Hz), 7.92 (1H, s), 8.02 (1H, dd, J=5.5, 7.9 Hz),8.54 (1H, d, J=8.3 Hz), 8.73 (1H, s), 9.02 (1H, dd, J=1.3, 5.3 Hz), 9.07(1H, d, J=7.53 Hz), 9.67 (1H, s).

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1. A fused azolepyrimidine derivative of the formula (I), its tautomericor stereoisomeric form, or a salt thereof:

wherein X represents CR⁵R⁶ or NH; Y¹ represents CR³ or N; Chemical bondbetween Y²═Y³ represents a single bond or double bond, with the provisothat when the Y²═Y³ represents a double bond, Y² and Y³ independentlyrepresent CR⁴ or N, and when Y²═Y³ represents a single bond, Y² and Y³independently represent CR³R⁴ or NR⁴; Z¹, Z², Z³ and Z⁴ independentlyrepresent CH, CR² or N; R¹ represents aryl optionally having 1 to 3substituents selected from R¹¹, C₃₋₈ cycloalkyl optionally having 1 to 3substituents selected from R¹¹, C₁₋₆ alkyl optionally substituted byaryl, heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one or morehalogen, C₁₋₆ alkoxy optionally substituted by carboxy, aryl,heteroaryl, C₁₋₆ alkoxyaryl, aryloxy, heteroaryloxy or one or morehalogen, or a 3 to 15 membered mono- or bi-cyclic heterocyclic ring thatis saturated or unsaturated, optionally having 1 to 3 substituentsselected from R¹¹, and contains 1 to 3 heteroatoms selected from thegroup consisting of N, O and S, wherein R¹¹ represents halogen, nitro,hydroxy, cyano, carboxy, amino, N—(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino,N-(formyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkanesulfonyl)amino,N-(carboxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, N—(C₁₋₆alkoxycabonyl)amino,N—[N,N-di(C₁₋₆alkyl)amino methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino(C₁₋₆alkyl)methylene]amino, N—[N,N-di(C₁₋₆alkyl)amino C₂₋₆alkenyl]amino,aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl, C₃₋₈cycloalkyl, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, C₁₋₆alkoxycarbonyl, N-arylamino whereinsaid aryl moiety is optionally having 1 to 3 substituents selected fromR¹⁰¹, N-(aryl C₁₋₆alkyl)amino wherein said aryl moiety is optionallyhaving 1 to 3 substituents selected from R¹⁰¹, aryl C₁₋₆alkoxycarbonylwherein said aryl moiety is optionally having 1 to 3 substituentsselected from R¹⁰¹, C₁₋₆alkyl optionally substituted by mono-, di- ortri-halogen, amino, N—(C₁₋₆alkyl)amino or N,N-di(C₁₋₆alkyl)amino,C₁₋₆alkoxy optionally substituted by mono-, di- or tri-halogen,N—(C₁₋₆alkyl)sulfonamide, or N-(aryl)sulfonamide, or a 5 to 7 memberedsaturated or unsaturated ring having 1 to 3 heteroatoms selected fromthe group consisting of O, S and N, and optionally having 1 to 3substituents selected from R¹⁰¹ wherein R¹⁰¹ represents halogen,carboxy, amino, N—(C₁₋₆ alkyl)amino, N,N-di(C₁₋₆alkyl)amino,aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl, pyridyl, C₁₋₆ alkyl optionallysubstituted by cyano or mono- di- or tri-halogen, and C₁₋₆alkoxyoptionally substituted by cyano, carboxy, amino, N—(C₁₋₆ alkyl)amino,N,N-di(C₁₋₆alkyl)amino, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)aminocarbonyl or mono-, di- or tri-halogen; R²represents hydroxy, halogen, nitro, cyano, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₁₋₆ acyloxy, aminoC₁₋₆acyloxy, C₂₋₆alkenyl, aryl, a 5-7 membered saturated or unsaturatedheterocyclic ring having 1 to 3 heteroatoms selected from the groupconsisting O, S and N, and optionally substituted by hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, oxo, amino, amino C₁₋₆alkyl, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, N—(C₁₋₆alkyl)carbonylamino,phenyl, phenyl C₁₋₆ alkyl, carboxy, C₁₋₆alkoxycarbonyl, aminocarbonyl,N—(C₁₋₆alkyl)aminocarbonyl, or N,N-di(C₁₋₆alkyl)amino, —C(O)—R²⁰ whereinR²⁰ represents C₁₋₆ alkyl, C₁₋₆ alkoxy, ammo, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, or a 5-7 membered saturatedor unsaturated heterocyclic ring having 1 to 3 heteroatoms selected fromthe group consisting O, S and N, and optionally substituted by C₁₋₆alkyl, C₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, phenyl, or benzyl, C₁₋₆alkyl optionally substituted by R²¹, or C₁₋₆ alkoxy optionallysubstituted by R²¹, wherein R²¹ represents cyano, mono-, di ortri-halogen, hydroxy, amino, N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆ alkyl)amino, N-(halophenylC₁₋₆ alkyl)amino, amino C₂₋₆alkylenyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkoxy, —C(O)—R²⁰¹, —NHC(O)—R²⁰¹,C₃₋₈cycloalkyl, isoindolino, phthalimidyl, 2-oxo-1,3-oxazolidinyl, arylor a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1to 4 heteroatoms selected from the group consisting O, S and N, andoptionally substituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, hydroxyC₁₋₆ alkoxy, oxo, amino, aminoC₁₋₆alkyl,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino, orbenzyl, wherein R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(halophenylC₁₋₆ alkyl)amino, C₁₋₆alkyl,aminoC₁₋₆ alkyl, aminoC₂₋₄ alkylenyl, C₁₋₆ alkoxy, a 5 or 6 memberedsaturated or unsaturated heterocyclic ring having 1 to 4 heteroatomsselected from the group consisting O, S and N, and optionallysubstituted by hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl,hydroxyC₁₋₆ alkoxy, oxo, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆ acyl)amino or benzyl; R³ representshydrogen, halogen, aminocarbonyl, or C₁₋₆ alkyl optionally substitutedby aryl C₁₋₆ alkoxy or mono-, di- or tri-halogen; R⁴ represents hydrogenor C₁₋₆ alkyl; R⁵ represents hydrogen or C₁₋₆ alkyl; and R⁶ representshalogen, hydrogen or C₁₋₆ alkyl.
 2. The fused azolepyrimidine derivativeof the formula (I), its tautomeric or stereoisomeric form, or a saltthereof as claimed in claim 1, wherein X represents CR⁵R⁶ or NH; Y¹represents CR³ or N; Chemical bond between Y²═Y³ represents a singlebond or double bond, with the proviso that when the Y²═Y³ represents adouble bond, Y² and Y³ independently represent CR⁴ or N, and when Y²═Y³represents a single bond, Y² and Y³ independently represent CR³R⁴ orNR⁴; Z¹, Z², Z³ and Z⁴ independently represent CH, CR² or N; R¹represents C₁₋₆ alkyl optionally substituted by mono-, di- ortri-halogen, phenyl, methoxyphenyl, phenoxy, or thienyl, C₁₋₆ alkoxyoptionally substituted by mono-, di- or tri-halogen, phenyl,methoxyphenyl, phenoxy, or thienyl, or one of the following carbocyclicand heterocyclic rings selected from the group consisting ofcyclopropyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl,furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, isoimidazolyl, pyrazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole,1,3,4-triazole, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1-benzothiophenyl, benzothiazolyl, benzimidazolyl,3H-imidazo[4,5-b]pyridinyl, benzotriazolyl, indolyl, indazolyl,imidazo[1,2-a]pyridinyl, quinolinyl, and 1,8-naphthyridinyl, whereinsaid carbocyclic and heterocyclic rings optionally substituted With 1 to3 substituents selected from the group consisting of hydroxy, halogen,nitro, cyano, carboxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino, N—(C₁₋₆alkoxycarbonyl)amino,N-(formyl)-N—(C₁₋₆alkyl)amino, N[N,N-di(C₁₋₆alkyl)amino methylene]amino,N[N,N-di(C₁₋₆alkyl)amino (C₁₋₆alkylene)methylene]amino,N—[N,N-di(C₁₋₆alkyl)amino C₂₋₆alkenyl]amino, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, pyrrolyl,imidazolyl, pyrazolyl, pyrrolidinyl, pyridyl, phenyl C₁₋₆alkoxycarbonyl,thiazolyl optionally substituted by pyridyl, piperazinyl optionallysubstituted by C₁₋₆ alkyl or C₁₋₆alkoxy and C₁₋₆alkyl optionallysubstituted by mono-, di- or tri-halogen; R² represents hydroxy,halogen, nitro, cyano, carboxy, amino, N—(C₁₋₆ alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, C₂₋₆alkenyl, C₁₋₆alkoxycarbonyl,aminocaronyl, C₁₋₆acyloxy, aminoC₁₋₆ acyloxy, furyl, morpholino, phenyl,piperidino, aryl, pyrrolidinyl optionally substituted by C₁₋₆acylamino,piperidino optionally substituted by hydroxy, C₁₋₆ alkyl, carboxy,aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, orN,N-di(C₁₋₆alkyl)aminocarbonyl, piperazinyl optionally substituted byC₁₋₆ alkyl, C₁₋₆ alkyl optionally substituted by cyano, mono-, di- ortri-halogen, hydroxy, amino, N—(C₁₋₆alkyl)amino, N-hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, C₃₋₆ cycloalkyl, tetrazolyl,tetrahydropyranyl, morpholino, phthalimidyl, 2-oxo-1,3oxazolidinyl,phenyl, —C(O)—R²⁰¹, pyrrolidinyl optionally substituted byC₁₋₆acylamino, piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl, orN,N-di(C₁₋₆alkyl)aminocarbonyl, or piperazinyl optionally substituted byC₁₋₆ alkyl, wherein R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-halobenzyl)amino, C₁₋₆alkyl, C₁₋₆ alkoxy,tetrazolyl, tetrahydropyranyl, morpholino, pyrrolidinyl optionallysubstituted by C₁₋₆acylamino, piperidino optionally substituted byhydroxy, C₁₋₆ alkyl, carboxy, aminocarbonyl, N—(C₁₋₆alkyl)aminocarbonyl,or N,N-di(C₁₋₆alkyl)aminocarbonyl, or piperazinyl optionally substitutedby C₁₋₆ alkyl, C₁₋₆ alkoxy optionally substituted by cyano, mono-, di-or tri-halogen, hydroxy, C₁₋₆alkoxy, hydroxy C₁₋₆ alkoxy, amino,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino, pyrrolyl, tetrazolyl,tetrahydropyranyl, morpholino, phthalimidyl, 2-oxo-1,3oxazolidinyl,phenyl, —C(O)—R²⁰¹, pyrrolidinyl optionally substituted byC₁₋₆acylamino, piperidino optionally substituted by hydroxy, C₁₋₆ alkyl,carboxy, aminocarbonyl, N—(C1-6-alkyl)aminocarbonyl, orN,N-di(C1-6alkyl)aminocarbonyl, or piperazinyl optionally substituted byC₁₋₆ alkyl, wherein R²⁰¹ represents hydroxy, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(halobenzyl)amino, C₁₋₆ alkyl, C₁₋₆ alkoxy,amino C₂₋₆ alkylenyl, tetrazolyl, tetrahydropyranyl, morpholino,pyrrolidinyl optionally substituted by C₁₋₆acylamino, piperidinooptionally substituted by hydroxy, C₁₋₆ alkyl, carboxy, aminocarbonyl,N—(C₁₋₆alkyl)aminocarbonyl, or N,N-di(C₁₋₆alkyl)aminocarbonyl, orpiperazinyl optionally substituted by C₁₋₆alkyl; R³ represents hydrogen,halogen, C₁₋₆ alkyl optionally substituted by aminocarbonyl, arylC₁₋₆alkoxy, or mono-, di- or tri-halogen; R⁴ represents hydrogen or C₁₋₆alkyl; R⁵ represents hydrogen or C₁₋₆ alkyl; and R⁶ represents hydrogen,halogen or C₁₋₆ alkyl.
 3. The fused azolepyrimidine derivative of theformula (I), its tautomeric or stereoisomeric form, or a salt thereof asclaimed in claim 1, wherein X represents CR⁵R⁶ or NH; Y¹ represents N;Y² and Y³ represent CR³R⁴; Chemical bond between Y²═Y³ represents asingle bond. Z⁴ represents CH; Z¹, Z² and Z³ independently represent CH,CR² or N; R¹ represents C₁₋₆ alkyl optionally substituted by mono-, di-or tri-halogen, phenyl, methoxyphenyl, phenoxy, or thienyl, C₁₋₆ alkoxyoptionally substituted by phenyl phenoxy, thienyl or mono-, di- ortri-halogen, or one of the following carbocyclic and heterocyclic ringsselected from the group consisting of cyclopropyl, cyclopentyl,cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, furyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,isoimidazolyl, pyrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1-benzothiophenyl,benzothiazolyl, benzimidazolyl, 3H-imidazo[4,5-b]pyridinyl,benzotriazolyl, indolyl, indazolyl, imidazo[1,2-a]pyridinyl, quinolinyl,and 1,8-naphthyridinyl, wherein said carbocyclic and heterocyclic ringsoptionally substituted with 1 to 3 substituents selected from the groupconsisting of hydroxy, halogen, nitro, cyano, carboxy, amino,N—(C₁₋₆alkyl)amino, N-(hydroxy C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N—(C₁₋₆alkoxycarbonyl)amino,N-(formyl)-N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino(C₂₋₆alkenyl)amino, N—(C₁₋₆alkane)sulfonyl amino,N[N,N-di(C₁₋₆alkyl)amino methylene]amino, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, pyrrolyl,imidazolyl, pyrazolyl, pyrrolidinyl, pyridyl, phenyl C₁₋₆alkoxycarbonyl,thiazolyl optionally substituted by pyridyl, piperazinyl optionallysubstituted by C₁₋₆ alkyl or C₁₋₆alkoxy and C₁₋₆alkyl optionallysubstituted by mono-, di- or tri-halogen; R² represents halogen,hydroxy, nitro, cyano, amino, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,(C₂₋₆)alkenyl, C₁₋₆alkoxycarbonyl, aminocarbonyl, furyl, piperidino,morpholino, phenyl, pyrrolidinyl optionally substituted by N—(C₁₋₆acyl)amino, or N—(C₁₋₆alkyl)carbonylamino, piperidino optionallysubstituted by hydroxy, piperazinyl optionally substituted by C₁₋₆alkyl,phenylC₁₋₆alkyl, C₁₋₆alkoxycarbonyl, or aminocarbonyl; C₁₋₆ alkyloptionally substituted by amino, cyano, C₁₋₆alkoxycarbonyl, morpholino,or mono-, di- or tri-halogen, or C₁₋₆ alkoxy optionally substituted byhydroxy, cyano, carboxy, C₁₋₆ alkoxy, C₁₋₆ acyl, C₁₋₆alkoxycarbonyl,amino, N—(C₁₋₆₋alkyl)amino, N—(C₁₋₆alkyl)aminocarbonyl,N,N-di(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)aminocarbonyl, aminocarbonyl,aminoC₁₋₆ alkylcarbonyl, N-(halobenzyl)aminocarbonyl, hydroxy C₁₋₆alkoxy, C₃₋₆ cycloalkyl, morpholino, morpholinocarbonyl, pyrrolidinyl,pyrrolyl, piperidino, phthalimidyl, or piperazinyl optionallysubstituted by benzyl; R³ represents hydrogen; R⁴ represents hydrogen;R⁵ represents hydrogen; and R⁶ represents hydrogen.
 4. The fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof as claimed in claim 1, wherein Xrepresents CR⁵R⁶ or NH; Y¹ represents N; Y² and Y³ represent CR³R⁴;Chemical bond between Y²═Y³ represents a single bond Z⁴ represents CH;Z¹, Z² and Z³ independently represent N, CH or CR²; R¹ representscyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl,pyrimidinyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl,1,3-benzothiazolyl, quinolyl, 3H-imidazo[4,5-b]pyridinyl, 1H-pyrrol-2-yloptionally substituted by C₁₋₆alkyl, 1H-pyrrol-3-yl optionallysubstituted by C₁₋₆alkyl, pyrazolyl optionally substituted by 1 or 2C₁₋₆alkyl, isoxazolyl optionally substituted by 1 or 2 C₁₋₆alkyl,2-thienyl optionally substituted by chloro, nitro, cyano, or C₁₋₆alkyl,3-thienyl optionally substituted by chloro, nitro, cyano, or C₁₋₆ alkyl,piperidinyl optionally substituted by C₁₋₆alkoxycarbonyl, orbenzyloxycarbonyl, phenyl optionally substituted by 1 to 3 substituentsselected from the group consisting of fluoro, chloro, hydroxy, nitro,cyano, carboxy, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, amino,N—(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino, N—(C₁₋₆alkoxycabonyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(formyl)-N—C₁₋₆alkyl amino, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, andpiperazinyl optionally substituted by C₁₋₆alkyl, pyridyl optionallysubstituted by 1 or 2 substituents selected from the group consisting ofchloro, hydroxy, carboxy, C₁₋₆alkoxy, C₁₋₆alkylthio, amino,N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N—(C₁₋₆alkane)sulfonyl amino,N[N,N-di(C₁₋₆alkyl)amino methylene]amino, and C₁₋₆alkyl optionallysubstituted by tri halogen, pyrazinyl optionally substituted byC₁₋₆alkyl, 1,3-thiazolyl optionally substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆alkyl, pyridyl andN—(C₁₋₆alkoxycarbonyl)amino, indolyl optionally substituted byC₁₋₆alkyl, benzimidazolyl optionally substituted by C₁₋₆alkyl ortri-halo C₁₋₆alkyl, 1,2,3-benzotriazolyl optionally substituted byC₁₋₆alkyl, 1,8-naphthyridinyl optionally substituted by C₁₋₆alkyloptionally substituted by tri halogen, C₁₋₆ alkyl optionally substitutedby tri-halogen, phenyl, phenoxy, or thienyl, or C₁₋₆alkoxy optionallysubstituted by phenyl, phenoxy, or thienyl; R² represents fluoro,chloro, bromo, hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, 2-furyl, piperidino,morpholino, phenyl, pyrrolidinyl optionally substituted by acetamido,piperidino optionally substituted by hydroxy, piperazinyl optionallysubstituted by methyl, benzyl, C₁₋₆alkoxycarbonyl, or aminocarbonyl,C₁₋₆ alkyl optionally substituted by cyano, tri-fluoro, carboxy,methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl,or morpholino, C₁₋₆ alkoxy optionally substituted by hydroxy, cyano,methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl,dimethylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, isopropylaminocarbonyl,fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, piperidino,tetrahydropyranyl, morpholino, morpholinocarbonyl,2-oxo-1,3-oxazolidin-4-yl, phthalimid-N-yl, or hydroxy C₁₋₆ alkyleneoxy,R³ represents hydrogen; R⁴ represents hydrogen; R⁵ represents hydrogen;and R⁶ represents hydrogen.
 5. The fused azolepyrimidine derivative ofthe formula (I), its tautomeric or stereoisomeric form, or a saltthereof as claimed in claim 1, wherein X represents CR⁵R⁶ or NH; Y¹represents N; Y² and Y³ represent CR³R⁴; Chemical bond between Y²═Y³represents a single bond Z³ and Z⁴ represent CH; Z¹ and Z² independentlyrepresent CH or CR²; R¹ represents cyclopropyl, cyclopentyl, cyclohexyl,2-furyl, 3-furyl, imidazolyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl,pyrimidinyl, pyridazinyl, piperazinyl, 1,2,3-thiadiazolyl,1,3-benzothiazolyl, quinolyl, 3H-imidazo[4,5-b]pyridinyl, pyrrolyloptionally substituted by C₁₋₆alkyl, pyrazolyl optionally substituted by1 or 2 C₁₋₆alkyl, isoxazolyl optionally substituted by 1 or 2 C₁₋₆alkyl,2-thienyl optionally substituted by chloro, nitro, cyano, or C₁₋₆ alkyl,3-thienyl optionally substituted by chloro, nitro, cyano, or C₁₋₆ alkyl,piperidinyl optionally substituted by C₁₋₆alkoxycarbonyl, orbenzyloxycarbonyl, phenyl optionally substituted by 1 to 3 substituentsselected from the group consisting of fluoro, chloro, hydroxy, nitro,cyano, carboxy, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, amino,N—(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino, N—(C₁₋₆alkoxycabonyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(formyl)-N-C₁₋₆alkyl amino, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, andpiperazinyl optionally substituted by C₁₋₆alkyl, pyridyl optionallysubstituted by 1 or 2 substituents selected from the group consisting ofchloro, hydroxy, carboxy, C₁₋₆alkoxy, C₁₋₆alkylthio, amino,N—(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N—(C₁₋₆alkane)sulfonyl amino,N[N,N-di(C₁₋₆alkyl)amino methylene]amino, and C₁₋₆alkyl optionallysubstituted by tri halogen, pyrazinyl optionally substituted byC₁₋₆alkyl, 1,3-thiazolyl optionally substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆alkyl, pyridyl andN—(C₁₋₆alkoxycrbonyl)amino, indolyl optionally substituted by C₁₋₆alkyl,benzimidazolyl optionally substituted by C₁₋₆alkyl or tri-haloC₁₋₆alkyl, 1,2,3-benzotriazolyl optionally substituted by C₁₋₆alkyl,1,8-naphthyridinyl optionally substituted by C₁₋₆alkyl optionallysubstituted by tri halogen, C₁₋₆ alkyl optionally substituted bytri-halogen, phenyl, phenoxy, or thienyl, or C₁₋₆alkoxy substituted byphenyl, phenoxy, or thienyl; R² represents fluoro, chloro, bromo,hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy, N—(C₁₋₆alkyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino,2-furyl, piperidino, morpholino, phenyl, pyrrolidinyl optionallysubstituted by acetamido, piperidino optionally substituted by hydroxy,piperazinyl optionally substituted by methyl, benzyl,C₁₋₆alkoxycarbonyl, or aminocarbonyl, C₁₋₆ alkyl optionally substitutedby cyano tri-fluoro, carboxy, methoxycarbonyl, aminocarbonyl,tert-butoxycarbonyl, tetrahydropyranyl, or morpholino, or C₁₋₆ alkoxyoptionally substituted by hydroxy, cyano, methoxy, methoxycarbonyl,tert-butoxycarbonyl, carboxy, aminoacetyl, dimethylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl,fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, piperidino,tetrahydropyranyl, morpholino, morpholinocarbonyl,2-oxo-1,3-oxazolidin-4-yl, phthalimid-N-yl, or hydroxy C₁₋₆ alkyleneoxy;R³ represents hydrogen; R⁴ represents hydrogen; R⁵ represents hydrogen;and R⁶ represents hydrogen.
 6. The fused azolepyrimidine derivative ofthe formula (I), its tautomeric or stereoisomeric form, or a saltthereof as claimed in claim 1, X represents CR⁵R⁶ or NH; Y¹ representsN; Y² and Y³ represent CR³R⁴; Chemical bond between Y²═Y³ represents asingle bond Z¹ and Z⁴ represent CH; Z² and Z³ independently represent CHor CR²; R¹ represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl,3-furyl, imidazolyl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, pyrimidinyl,piperazinyl, pyridazinyl, 1,2,3-thiadiazolyl, 1,3-benzothiazolyl,quinolyl, 3H-imidazo[4,5-b]pyridinyl, pyrrolyl optionally substituted byC₁₋₆alkyl, pyrazolyl optionally substituted by 1 or 2 C₁₋₆alkyl,isoxazolyl optionally substituted by 1 or 2 C₁₋₆alkyl, 2-thienyloptionally substituted by chloro, nitro, cyano, or C₁₋₆ alkyl, 3-thienyloptionally substituted by chloro, nitro, cyano, or C₁₋₆ alkyl,piperidinyl optionally substituted by C₁₋₆alkoxycarbonyl, orbenzyloxycarbonyl, phenyl optionally substituted by 1 to 3 substituentsselected from the group consisting of fluoro, chloro, hydroxy, nitro,cyano, carboxy, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, amino,N—(C₁₋₆alkyl)amino, N—(C₁₋₆acyl)amino, N—(C₁₋₆alkoxycabonyl)amino,N,N-di(C₁₋₆alkyl)amino, N-(formyl)-N—C₁₋₆alkyl amino, C₁₋₆ alkylthio,C₁₋₆alkanesulfonyl, sulfamoyl, pyrrolyl, imidazolyl, pyrazolyl, andpiperazinyl optionally substituted by C₁₋₆alkyl, pyridyl optionallysubstituted by 1 or 2 substituents selected from the group consisting ofchloro, hydroxy, carboxy, C₁₋₆alkoxy, C₁₋₆alkylthio, amino,N—(C₁₋₆alkyl)amino, N-hydroxyC₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N—(C₁₋₆acyl)amino, N—(C₁₋₆alkane)sulfonyl amino,N[N,N-di(C₁₋₆alkyl)amino methylene]amino, C₁₋₆₋alkoxyphenylC₁₋₆alkoxy,and C₁₋₆alkyl optionally substituted by tri halogen, pyrazinyloptionally substituted by C₁₋₆alkyl, 1,3-thiazolyl optionallysubstituted by 1 or 2 substituents selected from the group consisting ofC₁₋₆alkyl, pyridyl and N—(C₁₋₆₋alkoxycrbonyl)amino, indolyl optionallysubstituted by C₁₋₆alkyl, benzimidazolyl optionally substituted byC₁₋₆alkyl or tri-halo C₁₋₆alkyl, 1,2,3-benzotriazolyl optionallysubstituted by C₁₋₆alkyl, 1,8-naphthyridinyl optionally substituted byC₁₋₆alkyl optionally substituted by tri halogen, C₁₋₆ alkyl optionallysubstituted by tri-halogen, phenyl, phenoxy, or thienyl, or C₁₋₆alkoxysubstituted by phenyl, phenoxy, or thienyl; R² represents fluoro,chloro, bromo, hydroxy, nitro, vinyl, cyano, amino, aminoacetoxy,N—(C₁₋₆alkyl)amino, N,N-di(C₁₋₆alkyl)amino,N-(hydroxyC₁₋₆alkyl)-N—(C₁₋₆alkyl)amino, 2-furyl, piperidino,morpholino, phenyl, pyrrolidinyl optionally substituted by acetamido,piperidino optionally substituted by hydroxy, piperazinyl optionallysubstituted by methyl, benzyl, C₁₋₆alkoxycarbonyl, or aminocarbonyl,C₁₋₆ alkyl optionally substituted by cyano, tri-fluoro, carboxy,methoxycarbonyl, aminocarbonyl, tert-butoxycarbonyl, tetrahydropyranyl,or morpholino, or C₁₋₆ alkoxy optionally substituted by hydroxy, cyano,methoxy, methoxycarbonyl, tert-butoxycarbonyl, carboxy, aminoacetyl,dimethylamino, aminocarbonyl, methylaminocarbonyl,di-methylaminocarbonyl, isopropylaminocarbonyl,fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, piperidino,tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl,2-oxo-1,3-oxazolidin-4yl, phthalmid-N-yl, or hydroxy C₁₋₆ alkyleneoxy;R³ represents hydrogen; R⁴ represents hydrogen; R⁵ represents hydrogen;and R⁶ represents hydrogen.
 7. The fused azolepyrimidine derivative ofthe formula (I), its tautomeric or stereoisomeric form, or a saltthereof as claimed in claim 1, X represents CR⁵R⁶ or NH; Y¹ representsN; Y² and Y³ represent CR³R⁴; Chemical bond between Y²═Y³ represents asingle bond Z³ and Z⁴ represent CH; Z¹ and Z² independently represent CHor CR²; R¹ represents 3H-imidazo[4,5-b]pyridinyl, benzimidazolyl pyridyloptionally substituted by hydroxy, amino, acetamido, methoxybenzyloxy ormethylsulfonylamino, or 1,3-thiazolyl optionally substituted by 1 or 2methyl; R² represents fluoro, chloro, bromo, morpholino, piperazinyl,methylpeperazinyl, methyl, tri-fluoro methyl, or C₁₋₆ alkoxy optionallysubstituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl,tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl, orphthalimid-N-yl; R³ represents hydrogen; R⁴ represents hydrogen; R⁵represents hydrogen; and R⁶ represents hydrogen.
 8. The fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof as claimed in claim 1, Xrepresents CR⁵R⁶ or NH; Y¹ represents N; Y² and Y³ represent CR³R⁴;Chemical bond between Y²═Y³ represents a single bond; Z¹, Z³ and Z⁴represent CH; Z² represents CR²; R¹ represents3H-imidazo[4,5-b]pyridinyl, benzimidazolyl pyridyl optionallysubstituted by hydroxy, amino, acetamido, methoxybenzyloxy ormethylsulfonylamino, or 1,3-thiazolyl optionally substituted by 1 or 2methyl, R² represents fluoro, chloro, bromo, morpholino, piperazinyl,methylpeperazinyl, methyl, tri-fluoro methyl, C₁₋₆ alkoxy optionallysubstituted by hydroxy, cyano, carboxy, dimethylaminocarbonyl,tetrahydropyranyl, morpholino, morpholinocarbonyl, tetrazolyl, orphthalimid-N-yl; R³ represents hydrogen; R⁴ represents hydrogen; R⁵represents hydrogen; and R⁶ represents hydrogen.
 9. The fusedazolepyrimidine derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof as claimed in claim 1, whereinsaid derivative is selected from the group consisting of the followingcompounds:N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;6-(acetamido)-N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-{5-[2-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;2-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)-N,N-dimethylacetamide;2-[7-methoxy-8-(tetrahydro-2H-pyran-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;2-[8-(2-hydroxyethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)aceticacid;4-({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)butanoicacid;({5-[2-hydroxy-2-pyridin-3-ylvinyl]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)acetonitrile;2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;2-[7-methoxy-8-(4-morpholin-4-yl-4-oxobutoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1-pyridin-3-ylethylenol;5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-3-ol;N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;5-hydroxy-N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-[(4-methoxybenzyl)oxy]nicotinamide;N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-5-hydroxynicotinamide;5-hydroxy-N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;N-{8-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}nicotinamide;N-(7-bromo-8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;6-amino-N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;1-(1H-benzimidazol-5-yl)-2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-(2,4-dimethyl-1,3-thiazol-5-yl)ethylenol;N-(9-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-bromo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-(8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-[8-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;N-(7-fluoro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-(7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;N-(8-chloro-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;6-(acetamido)-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;1-(1H-benzimidazol-5-yl)-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)ethylenol;N-{5-[1-hydroxy-2-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)vinyl]pyridin-2-yl}acetamide;6-methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;1-(1H-benzimidazol-5-yl)-2-[8-(4-methylpiperazin-1-yl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]ethylenol;N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxamide;N-[7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1H-benzimidazole-5-carboxamide;N-(7,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1H-benzimidazole-5-carboxamide;N-{5-[2-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;N-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide;and2-(8,9-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-1-pyridin-3-ylethylenol;10. A medicament comprising the fused azolepyrimidine derivative, itstautomeric or stereoisomeric form, or a physiologically acceptable saltthereof as claimed in claim 1 as an active ingredient.
 11. Themedicament as claimed in claim 10, further comprising one or morepharmaceutically acceptable excipients.
 12. The medicament as claimed inclaim 10, wherein the fused azolepyrimidine derivative, its tautomericor stereoisomeric form, or a physiologically acceptable salt thereof isa PI3K inhibitor.
 13. The medicament as claimed in claim 10, wherein thefused azolepyrimidine derivative, its tautomeric or stereoisomeric form,or a physiologically acceptable salt thereof is a PI3K-γ inhibitor. 14.The medicament as claimed in claim 10 for prophylaxis and/or treatmentof inflammatory or immunoregulatory disorder.
 15. The medicament asclaimed in claim 14 for prophylaxis and/or treatment of asthma,rhinitis, allergic diseases, autoimmune pathologies, rheumatoidarthritis, Grave's disease, and atherosclerosis.
 16. The medicament asclaimed in claim 10 for prophylaxis and/or treatment ofneurodegenerative disorders, Alzheimer's disease, or focal ischemia. 17.The medicament as claimed in claim 10 for prophylaxis and/or treatmentof diabetes, cancer, myocardial contractility disorders, heart failure,ischemia, pulmonary hypertension, renal failure, or cardiac hypertrophy.18. Use of the fused azolepyrimidine derivative, its tautomeric orstereoisomeric form, or a physiologically acceptable salt thereof asclaimed in claim 1 for manufacturing a medicament for the treatmentand/or prevention of an inflammatory disorder or disease.
 19. Use of thefused azolepyrimidine derivative, its tautomeric or stereoisomeric form,or a physiologically acceptable salt thereof as claimed in claim 1 formanufacturing a medicament for the treatment and/or prevention ofasthma, rhinitis, allergic diseases, or autoimmune pathologies.
 20. Useof the fused azolepyrimidine derivative, its tautomeric orstereoisomeric form, or a physiologically acceptable salt thereof asclaimed in claim 1 for manufacturing a medicament for the treatmentand/or prevention of diabetes, cancer, myocardial contractilitydisorders, heart failure, ischemia, pulmonary hypertension, renalfailure, and cardiac hypertrophy.
 21. Use of the fused azolepyrimidinederivative, its tautomeric or stereoisomeric form, or a physiologicallyacceptable salt thereof as claimed in claim 1 for manufacturing amedicament for the treatment and/or prevention of disorder or diseaseassociated with PI3K activity.
 22. Use of the fused azolepyrimidinederivative, its tautomeric or stereoisomeric form, or a physiologicallyacceptable salt thereof as claimed in claim 1 for manufacturing amedicament for the treatment and/or prevention of disorder or diseaseassociated with PI3K-γ activity.
 23. Process for controlling aninflammatory disorder or disease in humans and animals by administrationof a PI3K inhibitory effective amount of a compound according toclaim
 1. 24. Process for controlling an inflammatory disorder or diseasein humans and animals by administration of a PI3K-γ inhibitory effectiveamount of a compound according to claim
 1. 25. Process for controllingan asthma, rhinitis, allergic diseases, or autoimmune pathologies, inhumans and animals by administration of a PI3K-γ inhibitory effectiveamount of a compound according to claim
 1. 26. Process for controlling adiabetes, cancer, myocardial contractility disorders, heart failure,ischemia, pulmonary hypertension, renal failure, and cardiachypertrophy, in humans and animals by administration of a PI3K-γinhibitory effective amount of a compound according to claim 1.